5 chapter 5

attachment

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Collishaw et al 2007

Abstract – King’s College London, MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK.

OBJECTIVE: Child abuse is an important risk for adult psychiatric morbidity. However, not all maltreated children experience mental health problems as adults. The aims of the present study were to address the extent of resilience to adult psychopathology in a representative community sample, and to explore predictors of a good prognosis. METHODS: Data are drawn from a follow-up of the Isle of Wight study, an epidemiological sample assessed in adolescence and at midlife. Ratings of psychiatric disorder, peer relationships and family functioning were made in adolescence; adult assessments included a lifetime psychiatric history, personality and social functioning assessments, and retrospective reports of childhood sexual and physical abuse. RESULTS: Ten percent of individuals reported repeated or severe physical or sexual abuse in childhood. Prospective measures revealed increased rates of adolescent psychiatric disorders in this group. Rates of adult psychopathology were also high.

A substantial minority of abused individuals reported no mental health problems in adult life. Resilience of this kind was related to perceived parental care,

adolescent peer relationships, the

quality of adult love relationships, and

personality style.

Good quality relationships across childhood, adolescence and adulthood appear especially important for adult psychological well being in the context of childhood abuse.

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Rikhye et al 2008

Abstract – Mood Disorders Research Program, Butler Hospital, Department of Psychiatry and Human Behavior, Brown Medical School, 345 Blackstone Boulevard., Providence, RI 02906, USA.

OBJECTIVE: The aim of this study was to examine associations between childhood adversity, parental bonding, gender, depressive symptoms, and quality of life in non-treatment-seeking adults from the community. METHOD: Effects of differential parental rearing were compared in adults who reported a high degree of childhood maltreatment (n=72) and those who reported no significant adverse events in childhood (n=69). Subjects completed retrospective measures of childhood maltreatment and perceived parenting style, as well as measures of current depressive symptoms and quality of life. RESULTS: The subjects without childhood maltreatment were younger [why didn’t they control for this with sample selection?] and endorsed less current depressive symptomatology than did subjects with childhood maltreatment. While the subjects without a history of maltreatment reported more “optimal” bonding experiences with their parents, the maltreatment group members were more likely to characterize their early parental bonding experiences in terms of “affectionless control” (p<.001 for both maternal and paternal parenting), “affectionate constraint” (p=.025 for maternal parenting and p=.004 for paternal parenting), or “weak or absent” bonding (p<.001 for both maternal and paternal parenting).

Results of a multiple regression analysis revealed that

overall quality of paternal care …

and current level of depressive symptoms …

were significant independent predictors of adult quality of life.

If they already had current depression, that IS a part of their adult quality of life – comparing WHAT?

Gender effects between subjects providing parental bonding data were limited to the group with childhood maltreatment. What were they?

CONCLUSION: These findings extend previous work documenting a relationship between early life maltreatment and suboptimal parental bonding, suggesting gender-specific effects of maternal and paternal care.

Effects of childhood maltreatment

on quality of life in adulthood

appear to be linked with the

quality of childhood paternal care

and the occurrence of depressive symptomatology in adulthood, suggesting possible targets for primary or secondary prevention.

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Jacobsen, Hibbs & Ziegenhain 2000

Abstract – University of Illinois at Chicago, USA.

Using a longitudinal sample of children, this study examined the relation between maternal Expressed Emotion (EE) and mother-child attachment disorganization at age 6 years. A nonclinical sample of 33 children (at ages 12 months and 18 months) from Berlin, Germany participated with their mothers in Ainsworth’s Strange Situation. Thirty-two children were again observed with their mothers at age 6 years in a standard laboratory attachment observation. At the time of the 6-year assessment, maternal EE was assessed based on a Five-Minute Speech Sample. Mothers also completed the Life Events Questionnaire, a measure of family stress, and the Present State Examination, a measure of maternal depression.

Maternal Expressed Emotion

was significantly linked to mother-child attachment security

at age 6 years.

Further analyses revealed that High EE was most closely linked to the disorganized attachment pattern at age 6 years, an at-risk attachment pattern that has been associated with intrusive and hostile maternal behavior. Are they talking about emotional acting out on the part of the mother?

The relationship was upheld when other relevant variables, including infant attachment disorganization and a measure of perceived family stress, were simultaneously considered. The study provides independent validation of Expressed Emotion as a measure of relationship quality in early childhood. It also provides a basis for the further investigation of the nature of the relation between maternal Expressed Emotion and attachment disorganization.

Hard to know where I need to draw the line between child maltreatment and attachment!

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Belsky & Fearon 2002

Abstract – Institute for the Study of Children, Families and Social Issues, Birkbeck University of London, UK. j.belsky@bbk.ac.uk

In light of evidence that the effects of attachment security on subsequent development may be contingent on the social context in which the child continues to develop, we examined the effect of attachment security at age 15 months, cumulative contextual risk from 1 to 36 months, and the interaction of attachment and cumulative risk to predict socioemotional and cognitive linguistic functioning at age 3 years, using data from the National Institute of Child Health and Human Development Study of Early Child Care. Results indicated that early attachment predicts both socioemotional development and language skills, but not cognitive functioning as indexed by a measure of school readiness, and that the effect of attachment on socioemotional development and expressive language varied as a function of social-contextual risk.

Insecure-avoidant infants proved most vulnerable to contextual risk, not children classified as secure or insecure more generally,

although in one instance security did prove protective with respect to the adverse effects of cumulative contextual risk. No idea how large their sample size was – this is a MAJOR effect from other research indicators

Findings are discussed in terms of risk and resilience and in light of the probabilistic nature of the relation between early attachment and later development.

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Easterbrooks, Biesecker & Lyons-Ruth 2000

Abstract – Eliot-Pearson Department of Child Development, Tufts University, Medford, MA 02155, USA. aeasterb@emerald.tufts.edu

This investigation examined the longitudinal prediction of emotional availability in mother-child interaction during middle childhood from two indicators of socioemotional functioning in infancy: security of infant-mother attachment; and maternal depressive symptoms. Forty-five children and their mothers were seen during infancy: security of attachment was assessed in the laboratory Strange Situation; and mothers completed a self-report of depressive symptoms. At age 7, children were observed with their mothers in a lab playroom. The dyad’s emotional availability was assessed during reunion following an hour-long separation. Results demonstrated significant associations between infancy and middle childhood socioemotional organization, both for mothers and for children.

Security of attachment in infancy was related to maternal sensitivity and structuring, and to child responsiveness and involvement at age 7. Maternal depressive symptoms in infancy were associated with maternal sensitivity and structuring at age 7.

Greatest differentiation was found between infants

with secure attachments

and those with insecure-disorganized attachments.

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Lemche et al 2006

Abstract – Division of Psychological Medicine, Section of Neuroscience and Emotion, Institute of Psychiatry, London, United Kingdom. e.lemche@iop.kcl.ac.uk

The neural basis of human attachment security remains unexamined. Using event-related functional magnetic resonance imaging (fMRI) and simultaneous recordings of skin conductance levels, we measured neural and autonomic responses in healthy adult individuals during a semantic conceptual priming task measuring human attachment security “by proxy”.

Performance during a stress but not a neutral prime condition was associated with response in bilateral amygdalae. Furthermore,

levels of activity within

bilateral amygdalae

were highly positively correlated with attachment insecurity

and autonomic response

during the stress prime condition. We thereby demonstrate a

key role of the amygdala in mediating autonomic activity associated with human attachment insecurity.

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Kennedy et al 2006

Abstract – Department of Psychiatry, University of Michigan, Ann Arbor 48109-0720, USA.

CONTEXT: There is extensive evidence implicating dysfunctions in stress responses and adaptation to stress in the pathophysiological mechanism of major depressive disorder (MDD) in humans.

Endogenous opioid neurotransmission

activating mu-opioid receptors

is involved in stress and emotion regulatory processes

and has been further implicated in MDD. OBJECTIVE: To examine the involvement of mu-opioid neurotransmission in the regulation of affective states in volunteers with MDD and its relationship with clinical response to antidepressant treatment. DESIGN: Measures of mu-opioid receptor availability in vivo (binding potential [BP]) were obtained with positron emission tomography and the mu-opioid receptor selective radiotracer carbon 11-labeled carfentanil during a neutral state. Changes in BP during a

sustained sadness challenge

were obtained by comparing it with the neutral state, reflecting changes in endogenous opioid neurotransmission during the experience of that emotion.

SETTING: Clinics and neuroimaging facilities at a university medical center. PARTICIPANTS: Fourteen healthy female volunteers and 14 individually matched patient volunteers diagnosed with MDD were recruited via advertisement and through outpatient clinics. INTERVENTIONS: Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion. Following imaging procedures, patients underwent a 10-week course of treatment with 20 to 40 mg of fluoxetine hydrochloride. MAIN OUTCOME MEASURES: Changes in mu-opioid receptor BP during neutral and sustained sadness states, negative and positive affect ratings, plasma cortisol and corticotropin levels, and clinical response to antidepressant administration.

The sustained sadness

condition was associated with a statistically significant

decrease in mu-opioid receptor BP in the

left inferior temporal cortex of patients with MDD

and correlated with negative affect ratings experienced during the condition. Conversely, a significant increase in mu-opioid receptor BP was observed in healthy control subjects in the rostral region of the anterior cingulate.

In this region rostral region of the anterior cingulate, a significant decrease in mu-opioid receptor BP during sadness was observed in patients with MDD who did not respond to antidepressant treatment.

Comparisons between patients with MDD and controls showed

significantly lower neutral-state mu-opioid receptor BP

in patients with MDD in the posterior thalamus,

correlating with corticotropin and cortisol plasma levels.

Larger reductions in mu-opioid system BP during sadness

were obtained in patients with MDD in the

anterior insular cortex,

anterior and posterior thalamus,

ventral basal ganglia,

amygdala, and

periamygdalar cortex.

The same challenge elicited larger increases in the BP measure in the control group in the

anterior cingulate,

ventral basal ganglia,

hypothalamus,

amygdala, and

periamygdalar cortex.

CONCLUSIONS: The results demonstrate differences between women with MDD and control women in mu-opioid receptor availability during a neutral state, as well as

opposite responses of this neurotransmitter system

during the experimental induction of a sustained sadness state.

These data demonstrate that

endogenous opioid neurotransmission

on mu-opioid receptors,

a system implicated in stress responses

and emotional regulation,

is altered in patients diagnosed with MDD.

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Liberzon et al 2007b

Abstract – Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0118, USA. liberzon@umich.edu

BACKGROUND: Functional neuroimaging studies have detected abnormal limbic and paralimbic activation to emotional probes in posttraumatic stress disorder (PTSD), but few studies have examined neurochemical mechanisms that underlie functional alterations in regional cerebral blood flow.

The mu-opioid neurotransmitter system,

implicated in responses to stress and suppression of pain,

is distributed in and is thought to regulate the function of

brain regions that are implicated in affective processing.

METHODS: Here we examined the micro-opioid system with positron emission tomography and the micro-opioid receptor-selective radiotracer [11C] carfentanil in 16 male patients with PTSD and two non-PTSD male control groups, with (n = 14) and without combat exposure (n = 15). Differences in micro-opioid receptor binding potential (BP2) were detected within discrete limbic and paralimbic regions.

RESULTS: Relative to healthy controls, both trauma-exposed groups had lower micro-opioid receptor BP2 in extended amygdala, nucleus accumbens, and dorsal frontal and insular cortex but had higher BP2 in the orbitofrontal cortex.

PTSD patients exhibited reduced BP2 in anterior cingulate cortex compared with both control groups.

Micro-opioid receptor BP2 in combat-exposed subjects without PTSD was lower in the amygdala but higher in the orbitofrontal cortex compared with both PTSD patients and healthy controls. CONCLUSIONS: These findings differentiate the general response of the micro-opioid system to trauma from more specific changes associated with PTSD. Interesting they call these “more general changes” when they are talking about the micro-molecular changes – nothing general about those changes?!

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Zubieta et al 2003

Abstract – Department of Psychiatry and Mental Health Research Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA. zubieta@umich.edu

Human affective responses appear to be regulated by limbic and paralimbic circuits.

However, much less is known about the

neurochemical systems engaged in this regulation. The

mu-opioid neurotransmitter system is distributed in,

and thought to regulate the function of,

brain regions centrally implicated in affective processing.

OBJECTIVE: To examine the involvement of mu-opioid neurotransmission in the regulation of affective states in healthy human volunteers. DESIGN: Measures of mu-opioid receptor availability in vivo were obtained with positron emission tomography and the mu-opioid receptor selective radiotracer [11C]carfentanil during a neutral state and during a sustained sadness state. Subtraction analyses of the binding potential maps were then performed within subjects, between conditions, on a voxel-by-voxel basis. SETTING: Imaging center at a university medical center. PARTICIPANTS: Fourteen healthy female volunteers. Intervention Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion. MAIN OUTCOME MEASURES: Changes in mu-opioid receptor availability and negative and positive affect ratings between conditions. Increases or reductions in the in vivo receptor measure reflect deactivation or activation of neurotransmitter release, respectively. RESULTS: The sustained sadness condition

was associated with a statistically significant deactivation

in mu-opioid neurotransmission in the

rostral anterior cingulate,

ventral pallidum,

amygdala, and

inferior temporal cortex.

This deactivation was reflected by increases in mu-opioid receptor availability in vivo. The

deactivation of mu-opioid neurotransmission in the

rostral anterior cingulate,

ventral pallidum, and

amygdala was

correlated with the increases in negative affect ratings

and the reductions in positive affect ratings

during the sustained sadness state.

CONCLUSIONS: These data demonstrate dynamic changes in mu-opioid neurotransmission in response to an experimentally induced negative affective state. The direction and localization of these responses

confirms the role of the mu-opioid receptor system in the physiological regulation of affective experiences in humans.

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Scott et al 2007b

Abstract – Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109-0720, USA.

This is a pilot examination of the hypothesis that some of the effects of smoking cigarettes in humans are mediated through nicotine activation of opioid and dopamine (DA) neurotransmission. Neuroimaging was performed using positron emission tomography and the radiotracers [11C]carfentanil and [11C]raclopride, labeling mu-opioid and DA D2 receptors, respectively. Six healthy male smokers were abstinent overnight. After radiotracer administration, subjects smoked two denicotinized cigarettes, followed 45 min later by two average nicotine cigarettes. Dynamic data were acquired over 90 min, and transformed into parametric maps of receptor availability in vivo (binding potential, BP), corresponding to low and high nicotine smoking periods and analyzed on a voxel-by-voxel basis using SPM’99 and correction for multiple comparisons. Significant activation of mu-opioid receptor-mediated neurotransmission from denicotinized to average nicotine conditions was observed in the right anterior cingulate cortex.

DA D2 [dopamine] neurotransmission

was activated in the ventral basal ganglia, correlating with Fagerström scale nicotine dependence scores.

Lower mu-opioid receptor BP was also detected during the denicotinized smoking condition in the smoker group, compared to baseline scans in non-smokers, in the cingulate cortex, thalamus, ventral basal ganglia, and amygdala. What does this mean?

These reductions were reversed during the average nicotine condition in the thalamus, ventral basal ganglia and amygdala.

These data point to both the feasibility of simultaneously examining opioid and DA neurotransmission responses to smoking in humans, as well as to the need to examine non-nicotine aspects of smoking to more fully understand the behavioral effects of this drug.

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Zak & Fakhar 2006

Abstract – Center for Neuroeconomics Studies, Claremont Graduate University, Claremont, CA 91711-6165, USA. paul@pauljzak.com

Social attachment is vital for human health and welfare. Recent experimental evidence in humans has identified the role of neuroactive hormones, especially the peptide oxytocin, in mediating trusting behaviors. Herein, we test if the endocrinological basis for trust between humans scales up to the country level. Trust pervades nearly every aspect of our daily lives, yet survey data on trust show substantial variation across countries.

Using 31 measures of biological, social, and environmental factors associated with hormone levels for a sample of 41 countries, we find that

two classes of factors are related to trust: consumption of plant-based estrogens (phytoestrogens), and the

presence of environmental conditions that include measures of estrogen-like molecules.

Our findings provide preliminary evidence that interpersonal trust at the country level may be related to the intake of neuroactive hormones.

phytoestrogen . A naturally occurring compound of plants, such as soybeans, or plant products, such as whole grain cereals, that acts like estrogen.

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Zak, Kurzban & Matzner 2004

Abstract – Center for Neuroeconomics Studies, Claremont Graduate University, Claremont, CA 91711-6165, USA. paul.zak@cgu.edu

This is the first report that endogenous oxytocin in humans is related to social behaviors, which is consistent with a large animal literature. Subjects are put into a social dilemma in which absent communication, cooperative behavior can benefit both parties randomly assigned to a dyad. The dilemma arises because one participant must make a monetary sacrifice to signal the degree of trust in the other before the other’s behavioral response is known. We show that receipt of a signal of trust is associated with a higher level of peripheral oxytocin than that in subjects receiving a random monetary transfer of the same average amount.

Oxytocin levels

were also related to trustworthy behavior

(sharing a greater proportion of the monetary gains).

We conclude that oxytocin

may be part of the human physiology

that motivates cooperation.

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Baumgartner et al 2008

Abstract – Center for the Study of Social and Neural Systems, Institute for Empirical Research in Economics, University of Zurich, Blumlisalpstrasse 10, CH-8006 Zurich, Switzerland. t.baumgartner@iew.uzh.ch

Trust and betrayal of trust are ubiquitous in human societies. Recent behavioral evidence shows that the neuropeptide oxytocin increases trust among humans, thus offering a unique chance of gaining a deeper understanding of the neural mechanisms underlying trust and the adaptation to breach of trust.

We examined the neural circuitry of trusting behavior by combining the intranasal, double-blind, administration of oxytocin with fMRI. We find that subjects in the oxytocin group show no change in their trusting behavior after they learned that their trust had been breached several times while subjects receiving placebo decrease their trust.

This difference in trust adaptation is associated

with a specific reduction in activation in the

amygdala, the

midbrain regions, and the

dorsal striatum in subjects receiving oxytocin,

suggesting that neural systems

mediating fear processing (amygdala and midbrain regions) and behavioral adaptations to feedback information (dorsal striatum) modulate oxytocin’s effect on trust.

These findings may help to develop deeper insights into mental disorders such as social phobia and autism, which are characterized by persistent fear or avoidance of social interactions.

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Zak, Kurzban & Matzner 2005

Abstract – Center for Neuroeconomics Studies, Claremont Graduate University, Claremont, CA 91711-6165, USA. paul@pauljzak.com

Human beings exhibit substantial interpersonal trust-even with strangers. The neuroactive hormone oxytocin facilitates social recognition in animals, and we examine if oxytocin is related to trustworthiness between humans. This paper reports the results of an experiment to test this hypothesis, where trust and trustworthiness are measured using the sequential anonymous “trust game” with monetary payoffs. We find that oxytocin levels are higher in subjects who receive a monetary transfer that reflects an intention of trust relative to an unintentional monetary transfer of the same amount. In addition, higher oxytocin levels are associated with trustworthy behavior (the reciprocation of trust).

Absent intentionality,

both the oxytocin and behavioral responses are extinguished. We conclude that perceptions of intentions of trust affect levels of circulating oxytocin.

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Petrovic et al 2008

Abstract – Wellcome Trust Functional Imaging Laboratory, University College London, London WC1N 3BG, United Kingdom. predrag.petrovic@ki.se

Social relations between humans critically depend on our affective experiences of others.

Oxytocin enhances prosocial behavior, but its effect on humans’ affective experience of others is not known.

We tested whether oxytocin influences affective ratings, and underlying brain activity, of faces that have been aversively conditioned. Using a standard conditioning procedure, we induced differential negative affective ratings in faces exposed to an aversive conditioning compared with nonconditioning manipulation. This

differential negative evaluative effect

was abolished by treatment with oxytocin,

an effect associated with an attenuation of activity

in anterior medial temporal and anterior cingulate cortices.

In amygdala and fusiform gyrus,

this modulation was stronger for faces with direct gaze,

relative to averted gaze,

consistent with a relative specificity for socially relevant cues.

The data suggest that oxytocin

modulates the expression of evaluative conditioning

for socially relevant faces via influences on amygdala and fusiform gyrus, an effect that may explain its prosocial effects.

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Guastella, Mitchell & Mathews 2008

Abstract – Brain & Mind Research Institute, University of New South Wales, Sydney, Australia. aguastella@med.usyd.edu.au

BACKGROUND: In nonhuman mammals, oxytocin has a critical role in social recognition and the development of long-term bonds. There has been limited research evaluating effects of oxytocin on the encoding and recognition of faces in humans. METHODS: In a double-blind, randomized, placebo-controlled, between-subject design, we administered oxytocin (24 IU) or a placebo to 69 healthy human male volunteers and then presented 36 happy, angry, or neutral human faces. Participants returned the following day to make “remember,” “know,” or “new” judgments for a mix of 72 new and previously seen faces.

Oxytocin-administered participants were more likely to make remember and know judgments for previously seen happy faces compared with angry and neutral human faces.

In contrast, oxytocin did not influence judgments for faces that had not been presented previously.

CONCLUSIONS: This study shows that the administration of oxytocin to male humans enhances the encoding of positive social information to make it more memorable.

Results suggest that oxytocin could enhance social approach, intimacy, and bonding in male humans by strengthening encoding to make the recall of positive social information more likely.

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Savaskan et al 2008

Abstract – Division of Psychiatry Research and Psychogeriatric Medicine, Psychiatric University Hospital, Minervastr. 145, P.O. 1682, CH-8032 Zürich, Switzerland. egemen.savaskan@puk.zh.ch

The nanopeptide oxytocin has physiological functions during labor and lactation. In addition, oxytocin is known to modulate aggression, anxiety, social behavior and cognition.

Little is known about its effects on memory for emotional stimuli. In the present single-blind, placebo-controlled, randomized study we have investigated the short- and long-term effects of a single post-learning dose (20 IU) of intranasal oxytocin on memory for facial identity and expression in 36 healthy young females and males using a face portrait recognition test. In the acquisition phase of the test, 60 different male faces with happy, angry or neutral expressions were presented to the volunteers. Thirty minutes and 24h after oxytocin administration, recognition memory tests were performed using portraits with neutral facial expressions, only.

Oxytocin improved identity recognition memory independently of participant’s gender, for neutral and angry faces, whereas this effect was not present for happy faces.

Oxytocin-treated subjects had a lower bias to judge not previously seen faces as being previously seen. Oxytocin had no effect on facial expression memory. In conclusion,

oxytocin has distinct effects on memory performance for facial identity and may contribute to the modulation of social behavior.

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Guastella et al 2008b

Abstract – Brain & Mind Research Institute, University of Sydney, Sydney, NSW 2050, Australia; School of Psychology, University of New South Wales, Sydney, Australia.

Oxytocin has a crucial role in social behavior, although its effects on social cognition are not fully understood. Past research shows that oxytocin enhances encoding and conceptual recognition of positive social stimuli over social-threat stimuli. Enhances the positive?

In this study, we evaluated whether oxytocin modified responses to positive and threatening social stimuli at an earlier perceptual stage of processing using the visual search task. In a double-blind, randomized, placebo-controlled, between-subject design, oxytocin (24 IU) or a placebo was administered to 104 healthy volunteers. Participants returned to complete the visual search paradigm 45min later. Results showed that angry faces were detected more efficiently than happy faces. Participants also gazed longer and more frequently toward angry faces.

Oxytocin did not, however, influence response time, accuracy, or gaze toward angry or happy faces, even when participants were separated into high- and low-social anxiety.

The results of this study suggest that oxytocin may not influence the detection of positive and threatening social stimuli at early perceptual levels of processing. Oxytocin may have greater influence in altering the cognitive processing of social valence at more conceptual and elaborate levels of processing.

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Kirsch et al 2005

Abstract – Cognitive Neuroscience Group, Center for Psychiatry and Psychotherapy, Justus-Liebig University, D-35385 Giessen, Germany.

In non-human mammals, the neuropeptide oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Aggression also moderated by vasopressin

Oxytocin reduces anxiety and

impacts on fear conditioning and extinction.

Recently, oxytocin administration in humans was shown to increase trust, suggesting involvement of the amygdala, a central component of the neurocircuitry of fear and social cognition that has been linked to trust and highly expresses oxytocin receptors in many mammals.

However, no human data on the effects of this peptide on brain function were available. Here, we show that

human amygdala function is strongly modulated by oxytocin.

We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. Compared with placebo,

oxytocin potently reduced activation of the amygdala

and reduced coupling of the amygdala to brainstem regions implicated in autonomic and behavioral

manifestations of fear.

Our results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain and provide a methodology and rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function has been implicated, such as social phobia or autism.

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Meyer-Lindenberg 2008

Abstract – Central Institute of Mental Health, Mannheim, Germany

Oxytocin and vasopressin are key effectors of social behavior (Insel, T. R. and Fernald, R. D. (2004). Annu. Rev. Neurosci., 27: 697-722). Oxytocin effects in humans were recently demonstrated by a behavioural study showing selectively increased trust after hormone administration (Kosfeld, M., et al. (2005). Nature, 435: 673-676). Since this suggested involvement of the amygdala, which is linked to trust (Winston, J. S., et al. (2002). Nat. Neurosci., 5: 277-283) – presumably because of its role in danger monitoring – and highly expresses oxytocin receptors (Huber, D., et al. (2005). Science, 308: 245-248), we studied amygdala circuitry after double-blind crossover intranasal application of placebo or oxytocin (Kirsch, P., et al. (2005). J. Neurosci., 25: 11489-11493).

Oxytocin potently reduced amygdala activation and decreased coupling to brainstem regions implicated in autonomic and behavioural manifestations of fear, indicating a neural mechanism for the effects of oxytocin in social cognition in humans and providing a potential therapeutic approach to social anxiety currently being tested in social phobia and autism. Furthermore, these data suggested a translational genetic approach. Preliminary findings (data not presented) from our laboratory using imaging

genetics indeed implicate genetic variants for both

AVPR1A,

encoding the primary receptor of vasopressin in brain, and the oxytocin receptor,

OXTR,

in amygdala regulation and activation.

Taken together, our results indicate neural mechanisms for human social behavior mediating genetic risk for autism through an impact on amygdala signaling and provide a rationale for exploring therapeutic strategies aimed at abnormal amygdala function in this disorder and in social dysfunction in general.

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Domes et al 2007

Abstract – Department of Psychiatry and Psychotherapy, University of Rostock, Rostock, Germany. gregor.domes@med.uni-rostock.de

Oxytocin is known to reduce anxiety and stress in social interactions as well as to modulate approach behavior. Recent studies suggest that the amygdala might be the primary neuronal basis for these effects. METHODS: In a functional magnetic resonance imaging study using a double-blind, placebo-controlled within-subject design, we measured neural responses to fearful, angry, and happy facial expressions after intranasal application of 24 IU oxytocin compared with placebo. RESULTS: Oxytocin reduced right-sided amygdala responses to all three face categories even when the emotional content of the presented face was not evaluated explicitly. Exploratory whole brain analysis revealed modulatory effects in prefrontal and temporal areas as well as in the brainstem.

CONCLUSIONS: Results suggest a modulatory role of oxytocin on amygdala responses to facial expressions irrespective of their valence.

Reduction of amygdala activity to positive and negative stimuli might reflect reduced uncertainty about the predictive value

of a social stimulus and thereby

facilitates social approach behavior.

Connects to an article on cannabinoids doing amygdala reduction with faces

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Israel et al 2008

Abstract – Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel.

Converging evidence from both human and animal studies has highlighted the pervasive role of two neuropeptides, oxytocin (OXT) and arginine vasopressin (AVP), in mammalian social behaviors.

Recent molecular genetic studies of the human arginine vasopressin 1a (AVPR1a) and oxytocin (OXTR) receptors have strengthened the evidence regarding the role of these two neuropeptides in a range of normal and pathological behaviors

. Significant association between both AVPR1a repeat regions and OXTR single nucleotide polymorphisms (SNPs) with risk for autism has been provisionally shown which was mediated by socialization skills in our study. AVPR1a has also been linked to eating behavior in both clinical and non-clinical groups, perhaps reflecting the social and ritualistic side of eating behavior. Evidence also suggests that

repeat variations in AVPR1a are associated with two other social domains in Homo sapiens:

music and altruism.

AVPR1a was associated with

dance and musical cognition

which we theorize as reflecting the ancient role of this hormone in social interactions executed by vocalization, ritual movement and dyadic (mother-offspring) and group communication.

Because of the evolutionary development that is suspected for language as a social communication originating in grooming behavior, there must be an interaction genetically here

Finally, we have shown that individual differences in allocation of funds in the dictator game, a laboratory game of pure altruism, is predicted by length of the AVPR1a RS3 promoter-region repeat echoing the mechanism of this hormone’s action in the vole model of affiliative behaviors and facilitation of positive group interactions.

While still in its infancy, the current outlook for molecular genetic investigations of AVP-OXT continues to be fascinating. Future studies should profitably focus on pharmacogenomic and genomic imaging strategies facilitated by the ease and efficacy of manipulating AVP-OXT neurotransmission by intranasal administration. Importantly, physiological measures, behavioural paradigms and brain activation can be informed by considering between-group and also within-group individual differences defined by common polymorphisms. Ultimately, investigators should strive to develop a cohesive model explaining how genomic variations are translated into individual and group differences in higher-order social behaviors.

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Depue & Morrone-Strupinsky 2005

Abstract – Laboratory of Neurobiology of Temperament and Personality, Department of Human Development, Cornell University, Ithaca, NY 14853, USA. rad5@cornell.edu

Because little is known about the human trait of affiliation, we provide a novel neurobehavioral model of affiliative bonding. Discussion is organized around processes of reward and memory formation that occur during approach and consummatory phases of affiliation.

Appetitive and consummatory reward processes

are mediated independently by the activity of the

ventral tegmental area (VTA) dopamine (DA)-nucleus accumbens shell (NAS) pathway

and the central corticolimbic projections of the u-opiate system of the medial basal arcuate nucleus, respectively, although

these two projection systems functionally interact across time.

We next explicate the manner in which DA and glutamate interact in both the

VTA and NAS to form incentive-encoded contextual memory ensembles that are predictive of reward derived from affiliative objects.

Affiliative stimuli, in particular,

are incorporated within contextual ensembles

predictive of affiliative reward via:

(a) the binding of affiliative stimuli in the rostral circuit of the medial extended amygdala and subsequent transmission to the NAS shell;

(b) affiliative stimulus-induced opiate potentiation of DA processes in the VTA and NAS; and

(c) permissive or facilitatory effects of gonadal steroids, oxytocin (in interaction with DA), and vasopressin on (i) sensory, perceptual, and attentional processing of affiliative stimuli and (ii) formation of social memories.

Among these various processes, we propose that the capacity to experience affiliative reward via opiate functioning

…..has a disproportionate weight in determining individual differences in affiliation. We delineate sources of these individual differences, and

provide the first human data

that support an association between

opiate functioning and

variation in trait affiliation.

++++

Gu & Yu 2007

Abstract – Neurobiology Laboratory and National Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, China.

Antinociceptive effects of oxytocin have been demonstrated in mice, rats, dogs, and humans. It has been shown that oxytocin receptors and fibers with oxytocin were distributed in the nucleus accumbens (NAc) of rats. The present study was performed to investigate the regulating role of oxytocin in nociception in the NAc of rats. Intra-NAc administration of oxytocin-induced dose-dependent increases in the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation in rats, indicating that oxytocin has antinociceptive effects in the NAc of rats.

Furthermore, the oxytocin-induced antinociceptive effects were attenuated by intra-NAc administration of the opioid-receptor antagonist naloxone, suggesting that

the endogenous opioid system is involved

in the oxytocin-induced antinociception in the NAc.

Moreover, the oxytocin-induced antinociception was attenuated by intra-NAc injection of the kappa-receptor antagonist nor-binaltorphimine (nor-BNI) and the mu-receptor antagonist beta-funaltrexamine, but not by the delta-receptor antagonist naltrindole, demonstrating the involvements of mu- and kappa-receptors, but not delta-receptor, in the oxytocin-induced antinociception in the NAc of rats. PERSPECTIVE: This article supplements the evidence that

oxytocin regulates nociception

in the central nervous system.

It presents additional material for clinical application of oxytocin as an analgesia drug.

++++

Gao & Yu 2004

Abstract – Laboratory of Neurobiology, College of Life Sciences, and National Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, PR China.

Recent studies showed that

oxytocin and opioid peptides

play important roles in pain modulation

at different levels in the central nervous system.

The present study was performed to explore whether opioid system is involved in the oxytocin-induced antinociception in the brain of rats. The results showed that: (1) intracerebroventricular injection of oxytocin induced dose-dependent increases in hindpaw withdrawal latencies (HWL) to noxious thermal and mechanical stimulation in rats. (2) The antinociceptive effect of oxytocin was attenuated dose-dependently by intracerebroventricular injection of naloxone, indicating an involvement of opioid system in the oxytocin-induced antinociception. (3) It is interesting that the antinociceptive effect of oxytocin was attenuated by subsequent intracerebroventricular injection of the mu-opioid antagonist beta-funaltrexamine (beta-FNA) and the kappa-opioid antagonist nor-binaltorphimine (nor-BNI), but not the delta-opioid antagonist naltrindole. The results indicate that oxytocin plays an antinociceptive role in the brain of rats; mu- and kappa-opioid receptors, not delta-receptors, are involved in the oxytocin-induced antinociception in the central nervous system of rats.

++++

Wang, Lundeberg & Yu 2003

Abstract – Laboratory of Neurobiology, College of Life Sciences, Peking University, Beijing 100871, China.

Recent studies showed that oxytocin plays an important role in nociceptive modulation in the central nervous system. The present study was undertaken to investigate the role of oxytocin in antinociception in the nucleus raphe magnus (NRM) of rats and the possible interaction between oxytocin and the opioid systems. Intra-NRM injection of oxytocin induced dose-dependent increases in hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulation in rats. The antinociceptive effect of oxytocin was significantly attenuated by subsequent intra-NRM injection of the oxytocin antagonist 1-deamino-2-D-Tyr-(Oet)-4-Thr-8-Orn-oxytocin. Intra-NRM injection of naloxone dose-dependently antagonized the increased HWLs induced by preceding intra-NRM injection of oxytocin, indicating an

involvement of opioid receptors in oxytocin-induced antinociception in the nucleus raphe magnus (NRM) of rats.

Furthermore, the antinociceptive effect of oxytocin was dose-dependently attenuated by subsequent intra-NRM injection of the mu-opioid antagonist beta-funaltrexamine (beta-FNA), but not by the kappa-opioid antagonist nor-binaltorphimine (nor-BNI) or the delta-opioid antagonist naltrindole. The results demonstrated that oxytocin plays an antinociceptive role in the nucleus raphe magnus (NRM) of rats through activating the oxytocin receptor.  Is the mu receptor the oxytocin receptor? Moreover, mu-opioid receptors, not kappa and delta receptors, are involved in the oxytocin-induced antinociception in the nucleus raphe magnus (NRM) of rats.

++++

Kosfeld et al 2005

Abstract – University of Zurich, Institute for Empirical Research in Economics, Blumlisalpstrasse 10, CH-8006 Zurich, Switzerland.

Trust pervades human societies. Trust is indispensable in friendship, love, families and organizations, and plays a key role in economic exchange and politics. In the absence of trust among trading partners, market transactions break down. In the absence of trust in a country’s institutions and leaders, political legitimacy breaks down. Much recent evidence indicates that trust contributes to economic, political and social success. Little is known, however, about the biological basis of trust among humans. Here we show that intranasal administration of oxytocin, a neuropeptide that plays a key role in social attachment and affiliation in non-human mammals, causes a substantial increase in trust among humans, thereby greatly increasing the benefits from social interactions.

We also show that the effect of oxytocin on trust is not due to a general increase in the readiness to bear risks.

On the contrary, oxytocin specifically affects an individual’s willingness to accept social risks arising through interpersonal interactions.

These results concur with animal research suggesting an

essential role for oxytocin

as a biological basis of prosocial approach behavior.

I want some!

++++

Marazziti & Catena Dell’osso 2008 ======  get this article

Abstract – Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Pisa, Italy. dmarazzi@psico.med.unipi.it

Oxytocin (OT) is a neurohypophysial hormone synthesized in the paraventricular and supraoptic nuclei of the hypothalamus.

Although OT-like substances have been identified in all vertebrates, OT has been found only in mammals where it plays a major role in the onset and maintaining of behaviors which are typical of these animals, such as labor and lactation. Recently, several data have suggested the involvement of OT in the formation of infant attachment, maternal behavior, pair bonding and, more generally, in linking social signals with cognition, behaviors and reward. The aim of this paper was to review critically the role of OT in the regulation of different physiological functions and complex behaviors, as well as its possible involvement in the pathophysiology of some neuropsychiatric disorders. MEDLINE and PubMed (1972-2007) databases were searched for English language articles by using the following keywords: oxytocin, physiology, cognitive functions, attachment, psychopathology, psychiatric disorders. Papers were examined that addressed the following aspects of the OT system: synthesis and localization, receptors, physiology: In addition, latest findings showing abnormalities of OT and OT system in several neuropsychiatric disorders, including autism, obsessive-compulsive disorder, eating disorders, addiction, schizophrenia, post-traumatic stress disorder and Prader-Willy syndrome, will be also discussed together with the possible clinical use of OT or its analogues and/or antagonists.

++++

Heinrichs et al 2004

Abstract – Department of Clinical Psychology and Psychotherapy, University of Zürich, Zürichbergstrasse 43, CH-8044 Zürich, Switzerland. m.heinrichs@psychologie.unizh.ch

The neuropeptide oxytocin is essential for mammalian parturition and lactation. Recent animal studies suggest that

oxytocin is also implicated in the central nervous control of behavior including learning and memory.

There has been little investigation, however, of the impact of oxytocin on human memory. The purpose of this study was to investigate the effect of a single dose of intranasal oxytocin on implicit and explicit memory in humans. In a placebo-controlled, double-blind study, 38 healthy men were randomly assigned to receive intranasal oxytocin (24 IU) or placebo 50 min before the study phase (incidental learning). Memory was measured using three different memory tests: an implicit perceptual test (word stem completion), an implicit conceptual test (category-cued semantic association), and an explicit test (cued recall). Due to the reproductive-biological role of oxytocin and the impact of adequate environmental conditions for the stimulation of behavioral effects of oxytocin known from animal research, we used semantic word stimuli with reproduction-related vs. neutral meaning.

Oxytocin significantly impaired recall performance as compared with placebo treatment irrespective of the meaning of words in the cued recall test. In the implicit conceptual test, characterized by a deepened information processing, compared with placebo, oxytocin significantly impaired only the overall generation of associated target words with reproduction [as in sex or what?] relevant meaning, whereas no significant difference between oxytocin and placebo was obtained for neutral words. These findings concur with data from animal research suggesting that central oxytocin selectively influences memory performance depending on the kind of memory test used and, more importantly, the psychobiological relevance of stimuli.

++++

links here in the cannabinoid system

++++

Champagne & Meaney 2001

Abstract – Montreal

Considerable evidence demonstrates that the quality of the early environment influences patterns of development that, in turn, determine the health and productivity of the individual throughout their life span.

……….. However, the processes through which early life influences health are not clearly understood.

………….Through the activation of the hypothalamo-pituitary-adrenal (HPA) axis and corticotropin-releasing hormone (CRH) pathways, prolonged or exaggerated responses to stress have profound effects on physiological and cognitive functions.

Early maternal separation or handling of neonatal rats can program widespread and lifelong changes in various transmitter systems that regulate the HPA and CRH systems.

Our studies show that a high level of maternal licking/grooming, and arched-back nursing correlates with reduced CRH mRNA expression and enhanced glucocorticoid negative feedback, and lower stress responses in the adult.

This behavior is stably transmitted between generations and cross-fostering studies show that the

offspring inherit the behavior from the nursing mother and not the biological mother.

Such intergenerational transmission of maternal behavior is seen in rodents, primates and humans, and

……….may underlie adaptive changes in the HPA axis.

The neural basis of this inheritance pattern appears to reside in the central oxytocin system which determines features of maternal behavior.

Through these various adaptive neural mechanisms the environmental demand on the mother is reflected in the quality of maternal care to her offspring.

………….This, in turn, programs stress reactivity and maternal behavior patterns of the offspring.

……….This not only determines certain health outcomes but also establishes the relationships between mother and offspring in the next generation.

These findings suggest that for neurobiologists, the function of the family is an important level of analysis and the critical question is that of how environmental events regulate neural systems that mediate the expression of parental care.

+++++++

++++

I go through life with a chronic feeling, no matter what (and this is about the best I feel) – if you were deeply engrossed in listening to a beautiful song, all the way through, and it gets to the end and you know the last perfect note is coming and you wait for it.  And wait some more, and then wait your whole life and that perfect final note never comes.  It’s built into my relationships, which matter more to me than my own breath, and I’m always stuck there with that same feeling, that waiting that never gets completed.

That’s the feeling I have from having been abused from birth and from never being able to form a secure attachment in childhood.  The feeling that happens when nobody was there and my brain never got to form those connections.  There are those that say of what’s called Reactive Disordered children who have been removed from their abusive and neglectful environments too late to be able to form attachments, that there’s hope through the neurofeedback training, a form of biofeedback, that can exercise the attachment circuits.  Those experts say that the circuits were established in our brains before birth, and that the feedback exercises can reach those circuits, can stimulate them to form connections necessary to form an attachment relationship with others way past the time that one would have normally been allowed to access that kind of connectivity with other members of their species.

I don’t know if I’ll ever get to try that technique.  It’s not like it’s available to me in any more an accessible way than were adequate attachment relationships in the beginning of my life.

An infant is physically attached before birth, and once that umbilical cord is cut, the attachment is meant to continue, to strengthen, and to guide the development of the infant’s brain into a benevolent world.  The infant knows its mother’s voice, the rhythms of her movements and of her speech before it is born.  An infant that loses its mother after birth will grieve, no matter what positive circumstances it is placed into next.  That grieving needs to be recognized and respected.  With adequate attachments, the grief will leave.

If there are no adequate attachments post birth, an infant will grieve and continue to grieve, I believe, for the rest of its life.  But the human brain, as part of the body, will adapt to whatever breaches it experiences.  No attachment for an infant is a signal to its body and brain that the adjustment has to be made to continued life in a malevolent world.  These changes become hardwired into the infant’s growing brain/body and the result is the evolution of an entirely different brain than the one it would have had if attachments had been made.

It is as simple as that.  The malevolent brain allows the body’s wisdom to tell it how best to survive – what’s important and what’s not.  The body will react to preserve it’s own self as if the survival of the species depended on it.  The body has no other wisdom when presented with threat.  It will survive.  When left to its own devices, a body figures out from birth that it is alone in an insecure malevolent world.  It knows that everything threatens its life.  The brain takes no time to consider the development or existence of a self.  There is only the body as a self.  That was my scenario.

My mother became a violent pathological criminal borderline as a result of what happened to her as a child.  I did not.  My own understanding is that she was partly attached, insecurely attached, was a partially formed self separate from her body when something so traumatic happened to her between, I would say, the ages of 2 and 6, that her self-as-agent could not endure it, could not make sense of it, could not integrate it, was overwhelmed by it, and my mother’s mind-in-the-making was destroyed.  Her mind went over the edge, around the bend, across the great divide, and there was no salvation for her in this lifetime.

I don’t mean that in any religious sense.  I mean it literally.  Her body knew how to survive what her little burgeoning self could not endure.  They parted ways on the very early path of her life, and what she did to me was a result of it.  Appearances to all but my immediate family were that a person was at home in my mother’s body during her lifetime, but I wasn’t fooled then, nor am I fooled now.  What was really there was some kind of phenotype that allowed her to continue to exist in order to reproduce, thought the conflict at the same time was that her brain was registered in the malevolent world category, so at the same time she procreated, her instincts were telling her the world was dangerous.

Her brain told her that life was not going to continue past the present instant.  It told her that there weren’t enough resources to go around.  It told her it wasn’t a good time to bring children into the world.  In that world, leaving your offspring behind or killing all but the fittest would have been not perhaps have been the best option available to a clan of desperate people, but the only one.  Along that line I would suspect, as I was the first born daughter, that such an old genetic reaction (of course tempered by and entangled with the environment in our current world) would include a reliving of the ancient pattern of women killing off their own competition in a desperate vying to survive in a world without resources.

Although my father was not a violent offender himself, I will say that in looking at the patterns of what our ancient genetic survival capacities include, the physiological differences between men and women manifest themselves even today most often with women committing crimes within the smaller arena of their intimate family, and men tending to range further (though of course their animosities include offense within the family) to commit crimes to the larger “audience” of the public.  I would not rule out that genetic survival-based malevolent-world brain formation reactions manifest the ancient male response to what is threatening the survival of their family or clan:  gain territory and supplies, kill the enemy and rape women – not always in that order, probably necessity-based preference being as close to doing all at the same time as possible.

We need not necessarily choose to remain mystified by some of the behavior we see manifested around us, particularly when we can easily determine the nature and malevolent influences in  someone’s utero, postnatal and childhood experiences if we look for them.

Lest you believe that my assessment of possible body-based (including brain developmental changes) that can happen to men and women, be fantasy or empty analogy, let me remind you of recent research findings being found in response to the American Psychiatric Society’s request that, in ongoing preparation for the revision of the Diagnostic and Statistical Manual for the upcoming fifth edition, serious attempts need to be made to discover and uncover ways in which genetic links to what we call mental illness might be able to manifest today.

As examples of how we carry our ancestral survival genes within us, ready to manifest in those that carry them when the body decides there is enough threat to survival to require them, are two genetic links found in connection to the fear response in modern humans. Although nobody would call these “mental illnesses,” these examples will resonate with many of you who either have personal experience with them, or know someone else who does.  This information can give us an idea of how simple the picture would look if we were standing back far enough in our history, even 300,000 to 20,000 years ago, well before anybody thought to label any available survival ability within our species as being unusual, let alone deviant.  We have to drop our childhood magical thinking and understand that just because we think the present world should be one way has nothing necessarily to do with how it actually is.

++++++

Informed Compassion

++

The spring before my 9^th birthday we were living in our Jamesway (portable, folding-ribbed military canvas housing shaped like a Quonset hut) on our Alaskan mountain homestead.  My father had added on 8 more 4-foot rib sections to the original five, each with two eight-foot floor boxes across the width.  Viewed from the higher hills above us, our home looked like a giant army-green worm with a round black chimney pipe sticking up at each end.

Although there were two small plastic windows with mesh in them in the plywood ends of our dwelling, there were no windows along the side walls making it always dark in the back where the canvas walls curved up over the triple bunk bed my father had constructed by shortening the legs of metal army beds and stacking all three together.  Mine was the top bunk because I was the oldest.  Sharon’s was the bottom because she was the youngest, and Cindy slept in the middle.

++

Late one rainy weekend afternoon my mother attacked me again.  I don’t remember why.  Perhaps I had forgotten to wipe off the top of the stove after I washed the dishes.  Perhaps mother had overheard me referring to her as “she” while talking to my siblings.  Perhaps she thought I was pouting, or that I didn’t answer her fast enough or loudly enough when she asked me a question.

But whatever it was that had happened, it ended with her hitting, punching, slapping, and beating me as she screamed her condemnations.  On her final blow she raised her right hand behind her left ear and swung with all her power hard and fast at my face and hit my nose.  Her screaming escalated until she finally crescendoed with, “Get out of my sight!  Go to bed without your dinner!  I can’t stand the sight of you!”  I escaped to the dim back of the Jamesway and crawled up to my bed, only now when out of her sight allowing myself to cry.

Cindy was sitting near the bed on the small straight backed wooden chair painted turquoise to match the bunk beds, supposedly color coordinated with the Pepto Bismal pink canvas walls of the Jamesway.  Eventually Cindy stood on the edge of the lower bunk and peered over the edge of my mattress.  She had been listening not only to my smothered sobs and sniffling, but to what must have struck her as an unusual sound, that of garbled choking.  “I’m going to get Mom,” she told me, though I couldn’t imagine why.  I did not want her to come near me, but Cindy ran off to get her anyway.

Mother complained loudly as she stomped back to my bed, her feet hitting hard on the hollow rough plywood boxes that constructed our floors.  She came because Cindy, her angel child, had insisted, though she was not pleased at the summons.  “Get out of that bed this instant,” she demanded when she saw me.  “Look at the terrible mess you’re making, Linda, blood all over the place!  You will have to clean this up!  Get up!”

But she did not yank me and I slid off the far foot end of the bed, as far from her as I could get, but she told me to sit on the little turquoise chair which put me right there by her legs.  She stopped yelling at me, though, and her voice changed when she called dad, who was now standing behind me, and told Cindy to go get the metal dishpan and a towel for me to put on my lap.  I sat with my head bent over the pan, blood flooding out of my nose, and no amount of criticism from mother or direction from father stemmed the flow.

Soon my brother, John, and sister, Sharon, were sitting on the floor close to my feet next to Cindy.  At first the blood made a high tinny plinking sound as it fell into the pan, but this sound soon deepened and then came as a very faint plop-plop.  I watched the bottom of the round white enamel dishpan with its red edging disappear under blood as my nose kept on bleeding.  A strange warm and cozy silence I had never heard before surrounded me.  For the first time in my life my family had me in its circle.  I felt connected and included.  I felt I belonged and the feeling of being wanted and cared about and of not being in trouble for those rarest of moments is a memory that is carried in my body, reawakens and resonates with any similar feeling that comes to me today connected to people I care about.

It would not have been impossible for my parents to take me down the mountain jeep road to get medical attention, but the trip would have taken hours and my father didn’t believe that such a journey was necessary.  I guess both my parents were content to stand there watching their daughter bleed to death because by the time my nose finally quit bleeding the dishpan was nearly a third full.  But that feeling I was experiencing for the first time in my life was so beautiful to me and so precious that even if I had understood the threat of death I was under, I would gladly have paid that price for that sense of connection I translated into what it feels like to be loved.

I consider this memory especially important because, as my sister, Cindy, reminded me, I need to remember that PTSD carries the potential for positive trauma feelings of comfort and security to be reenacted in our present lives just as the negative feelings are.  These memories, deeply implanted in our body’s cells as implicit memories, are out of the range of our conscious explicit awareness, but can run our lives as surely as a giant water wheel paddling through a crystal clear stream, connected to some massive grinding stone in a mill, can turn grain into flour that goes into the bread our lives are made from.

Having suffered nearly constant peritrauma for the first 18 years of my life prepared me to actually feel fortunate to have had the experience I tell you of now.  Without it I might never have known what that sense of being connected and cared for as a part of my family could possibly have felt like.  That abiding sense of human comfort and security I felt that day should have been my birthright, but it wasn’t.  It is a testament to the wonder of human resiliency that I was able to build on that one day’s experience of what felt like love to me for the rest of my life.

If I had not had that particular nosebleed, and that particular experience, perhaps I would never have known that glimmer of what the feeling of connection was supposed to be and could not have imagined it or recognized it later.  As this is one of the better memories of my childhood the rest of it, as you might guess, could have been written by the brothers Grimmer and Glummer..

++

Oh, and get used to this.  I will tell you once in a while throughout this book to smile!  I mean it!  Even a fake made-up-smile activates neurons in the tiny happy center of our left brain.  It’s excellent exercise, and reminds never to forget that any childhood we survived gives us a success story because life wants us to live, no matter what.

The tricky part is to realize that even though my mother ended up a psycho borderline, she did survive and my five siblings and I got to be born, along with our children and grandchildren.  My mother wasn’t born destined to be meaner than a 101 junkyard dogs.  Her heart was broken by trauma when she was very young and her mind adapted to that fact by finding a way for her to survive what she could not endure.

My heart cries for my mother as surely as it does for the young Iraqi veteran who died last weekend from huffing himself to death.  He had no way to survive the unbearable pain and suffering he could not endure.  I believe most of what we call mental illness is the body’s way of jumping over the hurdle that unbearable pain and suffering creates in a human psyche so that at least the survival of the body is better ensured.

It is because of the range of possibilities available within our species that created resiliency which in turn allows us to survive, even with a terribly broken heart from babyhood.  This is both our threat and our promise.  If we survive what we could not endure, this survival comes with a very high price and we may not have a preserved, intact ability to communicate with our self.

We can choose to celebrate this tenacity of life while in the midst of our own growing pains as we work to heal the same traumas that have been passed on to us from our ancestors.  I believe that unresolved traumas act very much like cancer cells do in that both have figured out how not to die.  It is their attempt at immortality that kills us.  The fact that their survival kills their hosts – in body or in mind – is of no concern to these malignancies. But traumas cycles continue because they have something to teach us as individuals and as a species.  Until we learn these lessons and adapt ourselves accordingly, some of us will be forced to continue paying a terrible price for survival.  Yet once we learn traumas’ lessons and allow ourselves to complete our healing trauma cycles, we will know they are no longer necessary.  In order to accomplish this feat, we need information, knowledge, consciousness, awareness, and self-reflection.

Yet I also believe it would be an act of foolish denial and childish magical thinking to believe that the consequences of severe trauma experienced before the age of five can ever be completely repaired. Traumas that occur during crucial brain and nervous system developmental stages of infancy and young childhood create entirely different brains.  It is impossible for these brains, created in and by and for a malevolent world, to ever fully adapt to life in a benevolent one.  This is not a fiction, folks.  It’s the bedrock truth.

Yet while the information we are about to consider is deadly serious, please, don’t forget to smile now and then!  This is the only kind of power, the power of positive benovolency, which can ever hope to bring healing to trauma.  Just as that one experience of feeling connected to my family had the power to change my life, all efforts we make toward resolving traumas will effect positive change past our widest imaginings.  We need you

+++++++++++++++++

So, let’s consider some research.

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Strathearn et al 2008

Abstract – Department of Neuroscience, Meyer Center for Developmental Pediatrics, Human Neuroimaging Laboratory, Clinical Care Center, Suite 1530, 6621 Fannin St, Houston TX 77030-2399, USA. lanes@bcm.edu

OBJECTIVES: Our goal was to determine how a mother’s brain responds to her own infant’s facial expressions, comparing happy, neutral, and sad face affect. METHODS: In an event-related functional MRI study, 28 first-time mothers were shown novel face images of their own 5- to 10-month-old infant and a matched unknown infant. Sixty unique stimuli from 6 categories (own-happy, own-neutral, own-sad, unknown-happy, unknown-neutral, and unknown-sad) were presented randomly for 2 seconds each, with a variable 2- to 6-second interstimulus interval. RESULTS:

Key dopamine-associated reward-processing regions of the brain were activated when mothers viewed their own infant’s face compared with an unknown infant’s face.

These included the ventral tegmental area/substantia nigra regions, the striatum, and frontal lobe regions involved in

(1) emotion processing (medial prefrontal, anterior cingulate, and insula cortex),

(2) cognition (dorsolateral prefrontal cortex), and

(3) motor/behavioral outputs (primary motor area).

Happy, but not neutral or sad own-infant faces, activated nigrostriatal brain regions interconnected by dopaminergic neurons, including the substantia nigra and dorsal putamen.

A region-of-interest analysis revealed that activation in these regions was related to positive infant affect (happy > neutral > sad) for each own-unknown infant-face contrast. CONCLUSIONS: When first-time mothers see their own infant’s face, an extensive brain network seems to be activated, wherein affective and cognitive information may be integrated and directed toward motor/behavioral outputs. Dopaminergic reward-related brain regions are activated specifically in response to happy, but not sad, infant faces. Understanding how a mother responds uniquely to her own infant, when smiling or crying, may be the first step in understanding the neural basis of mother-infant attachment.

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Derntl et al 2008

Abstract – MR Centre of Excellence, Medical University of Vienna, Vienna, Austria. bderntl@ukaachen.de

Converging evidence has accumulated that menstrual cycle and thus hormonal levels can affect emotional behavior, in particular facial emotion recognition. Here we explored the association of ovarian hormone levels and amygdala activation during an explicit emotion recognition task in two groups of healthy young females: one group was measured while in their follicular phase (n=11) and the other during their luteal phase (n=11). Using a 3T scanner in combination with a protocol specifically optimized to reliably detect amygdala activation we found significantly stronger amygdala activation in females during their follicular phase. Also, emotion recognition performance was significantly better in the follicular phase.

We observed significant negative correlations between progesterone levels and amygdala response to fearful, sad and neutral faces, further supporting a significant modulation of behavior and neural response by hormonal changes during the menstrual cycle.

From an evolutionary point of view this

significant influence of ovarian hormone level on emotion processing and an important neural correlate, the amygdala, may enable a higher social sensitivity in females during their follicular phase, thus facilitating socio-emotional behavior (and social interaction) which may possibly facilitate mating behavior as well.

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Bracha, et al 2007

National Center for Posttraumatic Stress Disorder, Pacific Islands Division Department of Veterans Affairs, Pacific Islands Health Care System, Honolulu, HI

Research agenda for 5^th edition of DSM-3, emphasizing “…need for more etiologically-based classification system, especially for stress-induced and fear-circuitry disorders.”

“Testable hypotheses based on threats to survival during particular segments of the human era of evolutionary adaptedness (EEA) may be useful in developing a brain-evolution-based classification for the wide spectrum of disorders which are mostly overconsolidationally such as PTSD, to fear-circuitry disorders which are mostly innate such as specific phobias.”

:The recently presented Paleolithic-human-warfare hypothesis posits that blood-injection phobia can be traced to a “survival (fitness) enhancing” trait, which evolved in some females of reproductive-age during the millennia of intergroup warfare in the Paleolithic EEA.”

“The study presented here tests the key a priori prediction of this hypothesis – that current blood-injection phobia will have higher prevalence in reproductive-age women than in post-menopausal women.”

1078 women and 646 men —  subjects, section of a diagnostic interview designed to test for blood and injection phobia

results:  3.3% in women aged 27-49, 1.1% in women over age 50

corresponding figures for males were 0.8% and 0.7%

CONCLUSIONS:

“This epidemiological study provides one source of support for the Paleolithic-human-warfare (Paleolithic-threat) hypothesis regarding the evolutionary (distal) [away from point of origin] etiology of bloodletting-related phobia, [needles, sight of blood, drawing of blood, etc.] and may contribute to a more brain-evolution-based DSM-V.”

of course, they suggest that this information can help toward developing drugs “preventative interventions for this common and sometimes disabling fear-circuitry disorder.”

Like we can’t find alternative ways to deal with things, like information as to the genetic roots?  The chemo nurse told me she’s lost 5 treatable patients in the last year because they were that afraid of needles — supposedly, though chemo is horrible in itself!

++++

++

Our bodies contain ancient genetic information carried within us from long ago – and so not very long ago – when there was little but threat of extinction moment-to-moment, breath to breath, birth to death.  When those memories are triggered, out bodies remember, and if left to their own direction, they will manifest whatever genetic material they contain that gives them information on how best to proceed when nothing else is available and resources have run out.  Having an independent self-willed choice making conscious self is a luxury.  The body will act as a last resort Lassie to lead our lives home in times of danger when everything else has failed.

What happens when our self-as-agent is forced to abandon ship – when the body tells us “Captain oh captain, I need you not.  I have life preservation to think about now.  That’s it, no more questions, no more answers?”  What happens when our bodies leave our self standing forlornly at the station and takes off without us?  When our bodies say, “That’s enough, this obviously isn’t working, I don’t need you?”

We can’t wisely despise what we so callously call mental illness.  The ability the body has of taking control over its own life in the worst of situations is perhaps the greatest gift our species carries within its gene pool, and this ability has carried our species forward through difficulties we cannot imagine with our modern minds.  That any environment could exist in our current times that could push the body to these extremes is something it pays us to consider.  If we want to scorn anything, let us scorn our refusal to accept the reality that some infants and children have to endure conditions that make these extreme physical adjustments by their bodies necessary – which of course includes their brains – to the circumstances of their infancy and their childhoods.

++

“It takes one to know one.”  Those of us abandoned, battered, abused, neglected from birth have always known there is something really important that we should be told, but nobody speaks the words.  There is a taboo against infant abuse that is so powerful it carries over into our unwillingness to consider that it exists, and into our inability and unwillingness to talk about it.  This book aims to shatter this taboo.  It aims to sensitize its readers so that the further ends of the trauma spectrum can be unveiled because those of us who experienced severe abuse and neglect from birth are at the highest possible risk for developing a PTSD.

Mathematical language includes more than just the positive numbers on the number line.  There are negative numbers as well.  Human attachment possibilities are the same way.  Effective coping with trauma requires that we have resources, and those resources have to include positive connections with people.  We are not educated about our attachment styles and patterns, though they are chiefly responsible for forming us as individuals and affect our coping abilities throughout our entire lifespan.

++++

The truth is that a consideration of attachment styles is the hardest for me to write about because it hits too close to the bone.  I am directly and personally entangled with both the past and future aspects of what goes so wrong.

I cannot describe any of the secure or other organized patterns of attachment adequately because I have no experience with them.  I cannot describe them from the inside of the paradigm because I am outside of what is normal or desirable, and I cannot get “there” from “here.”  This is the backwards and downside-up condition that motivates me to write this book in the first place.  I am very nearly at the bottom of the attachment continuum.  I am in the place that most writers write about from a “have not experienced” position.  I am doing it the other way around.

I cannot pretend to be like others when I consider these circumstances from within my own truth, knowledge, perspective and awareness.  All my life I have been forced to walk around the planet in this body LOOKING like I am a normal adult member of my species, when in fact, I am not.  It makes writing a book about what can happen in regard to trauma, dissociation and the evolution of PTSD nearly impossible for me – because I am already there.

Looking at attachment head on feels about like standing in the path of an oncoming train might.  Anyone with any self preservation would dodge and run.  Those in my situation are usually put in the footnote at the bottom of the page.  How dare I expand that footnote into a book and put normal people in their footnote at the bottom of my page?

I sense that I sense (!) that I am daring to overturn a taboo that silences those of us who have suffered traumatizing histories that are so far out of the norm of the human range of experience.  Traumas are to be shunned, even in their verbal descriptions.  We are on the fringe, or over the fringe, of what is allowable for discourse in our language.

Broca’s area organizes our verbal packets because it evolved to organize action packets.  The problem with trauma is that it leaves us without a “coherent action packet” of response.  It has overwhelmed our coping abilities and resources.

If those of us who have suffered severe trauma from birth were suddenly to acquire transparent bodies that allowed everyone to see how disorganized and incoherent our “inside self” really is, all would stand aghast or run in terror of contamination.  We have resonating brains.  We have brains structured to process much of social life through contagion.  We have to hide our internal state from others, and from ourselves if possible, to avoid social outcast as carriers of the intergeneration traumas of our species – that MIGHT be contagious.  Who would want to “catch” the brunt of what happened to us, of what we know inside about the terrors of life?

+++++++++++++++++

reading Liotti 2001

He is saying that by age 6 80% of children that demonstrated a disorganized attachment at age 1 and still show same by age 6, demonstrate either active controlling or caregiving to the attachment figure.

This information sets of an entire reverberating set of reactions inside of me.  Like following an invisible thread back to my beginnings, I know instantly that my deviation from this pattern puts me into another even smaller category.

Liotti is not saying what happens to the other 20%.  What is their attachment pattern of disorganization toward the cursed attachment figure – for this is a cursed pattern of attachment?  How is my case even more different still?  What do I know about this from the inside of me?

My mother’s interactions with me forced me into a completely passive role.  She cut me off at every possible pass so that I was isolated from her and from everyone else.  She put me into a place that prevented me from interacting with anyone.  She disempowered me.

My brain is categorizing into hierarchical structure where I fit into the pattern of being human.  For every “not it” I encounter I am shifted to yet another, lower position on the security scale.  Every notch I slip down from normal resonates with yet another level of pain and sorrow.  And yet at the same time I have to recognize my persistent courage in pursuing the truth, my truth, though it seems that I am walking down into every increasingly dangerous and threatening terrain.  What if there is a fissure down there that I have protected myself from that I can fall into in my present from which I will never again escape from?

This is a search to find out what Linda knows, as if this information is somehow useful and important, to be included in the grand scheme of what is possible for humans to endure.  What does primary and essential and foundational isolation coupled with pathological evil attribution do to a person’s mind-self/brain?

It is as if the further I slip from the norm I slip correspondingly into a place of the great psychic ooze of primordial non-awareness that is at the same time a closer connection to the wholeness of life.  I am motivated to NAME this, to give language to it, and I have to find IT before that can happen.

What does it mean to be cut off from one’s self, from all other humans, in mind even when the body is forced to continue its existence?  I gain increasing incrudularity/incredulousmess about the pervasiveness of mother’s controlling attacks on the essence of who I am.

I was obliterated.

My body existed.

I see in my mind’s eye the tentacles of her persistent drive to gain access and to destroy any manifestation within me of who I was/am.  Is it possible that her projection of herself into me could manifest with such depth, reaching so far into me that there was nowhere for me – as a being separate from her – to reside?  How far into deep and secret inner places did I have to run and hide from her?  How did I manage to preserve myself so that I remained intact separate from her?  Not in this material world – this all happened in some invisible world, the inner world, a different world from the one that we can measure and conscript into consciousness.

She engaged in pervasive elimination of me.  I must have been able to go underground, or underwater, to grow some kind of tendril root that was attached to myself, that could endure and survive without warmth or light until the 18-year sentence under her demising eye was completed.  How did I retain my self through all of that?  What and where were the life-giving cracks that she could not identify and then close, that let the light of life into my world?

When Liotti writes about a child controlling or caregiving the attachment figure, he is assuming that there is enough energy resource not consumed by the caregiver in the interaction so that the child can have at least a tiny portion of it to utilize it, to have it at its disposal.  My mother, like a gaping black hole, consumed and subsumed it all.

I have to hold onto, even now, the knowledge of a secure base that I had , somewhere and somehow within myself, that allowed me to retain a cohesiveness of self from birth or earlier, and that allowed me to come up for air, finally, when she could no longer take the air away from me.  I came up for light, attached to my own tendril root from birth, from conception, after she could no longer affect that root.  I had to grow more like a mint than a daisy.  (In Glyndon we had mint that sent root tendrils all the way from the south side of the house, under the house that came up on the north side.)

That tenacity of selfhood – do we all possess it?  Was it part of my destiny, being born a triple Virgo in the 12^th house, where my sun, my Venus, and my mercury – my core self, my passion and my mind all conjunct in Virgo submersed in the healing, “all is possible?” water house of Pisces?  I have to wonder……that is not chance, coincidence, happenstance, accident.  Yet what am I to learn from it, to make of it, to create of it that is good and useful to somebody else?

How did I circumvent my own elimination and annihilation?  How did I “go on being” as more than just a body?  Where was my mother in the midst of her actions toward me?  How could she be so persistent, consistent and determined, comprehensive?

Considering all of this makes me want to run away, to shed every part of my current life like a skin and go somewhere so beautiful and peaceful, to live a simple yet satisfying life in a place in the natural world where peace would come to me with every breath and wash over my skin and provide me with “peace that surpasses all understanding.”  It wants me to give up this futile and fruitless path toward finding anything beautiful and useless in my story. It makes me want to dismiss and avoid all contact with these old realities.  (Somehow I found this world through my experiential interactions with the homestead and the valley as a child.)

It makes me want to give up trying to articulate an experience for which there are no words.  And yet this very fact is indicative the of  “disordered attachment” in the world.  I continue to go through the process that is initiated with our conception, the defining of “me from not-me.”  I am in Liotti’s missing 20% of disorganized attachment, dissociating infants grown into an adult.  Let me go look for that missing population.  (Just like that children’s book, “Are you my mother?”)

It matters because the past never stops being a part of the future – the future which contains every ongoing instant of our present.  Mine is a process of continued differentiation of a self from the natural world, which I believe was possible for our species only because of some evolutionary process that each of us mirrors personally within the matrix of what is possible for our species as a whole.  (ontogeny recapitulates phylogeny)

But, instead of escaping to some beautiful place, I am going to immerse myself in a few hundred pages of research on disorganized infant attachment.  It is my choice today not to use a distractive and avoidant strategy, but to confront the situation head on.

I am searching for the underpinnings to dissociation.  I am searching for how trauma interrupts and interferes with the ongoing of a cohesive self.  And I am searching for the missing 20% of disorganized attachment people.  Because whatever caused the reaction to trauma, the end result is the same:  We are caught the rest of our lives stuck between approach and avoid.  Our nervous systems including our brains are altered.  How much of this can heal and how can the deterioration be prevented in late onset trauma?

But it is a difficult process to tolerate, this looking at disorganized attachment in the face and seeing myself there.

++++

McMahon, Dick 2005

Karpman (1968) described the drama triangle as consisting of three primary roles played in a pattern of interaction:

Persecutor

Rescuer

Victim

One-way controlling behavior, untested assumptions and inferences

(is this related to an inflexible ToM application?)

“An authentic relationship is one in which we take action based on our mutually determined understanding of the relationship and where each person feels free to make choices about actions to be taken.  In role relationships, we act on assumptions or inferences that we believe to be true but we have not tested.  Thus, we end up discounting the other person’s skills, abilities, or attitude, as well as his or her free choice.  In the context of this model, to discount means to deny the possibility that a capability, need, or feeling actually exists or to consider a capability, need, or feeling unimportant.”  McMahon 2005, p 422

the persecutor

“A person in the persecutor role (1) is critical of the actions of another person and either doesn’t understand the reasons behind the actions or attributes a negative intent to that person whether or not negative intent exists and (2) offers judgmental and nonspecific criticism.”  McMahon 2005, p 422

“The persecutor victimizes the other person by belittling the person or responding in ways that make that person feel inadequate, ashamed, or incompetent.  The persecutor feels righteous, vindicated, or responsible for dealing with the (422) situation.”  McMahon 2005, p 423

the rescuer

“A person in the rescuer role (1) discounts another person’s ability to handle his or her own problems and (2) attempts to “help” by doing for that person what he or she could and should do for himself or herself….The rescuer gets his or her needs met by appearing helpful, but the help actually creates a victim whose ability to take responsibility for his own actions has been discounted.  The approach also limits the learning opportunities of victims.”  McMahon 2005, p 423

the victim

“People in the victim role (1) discount their own ability, knowledge, or skill and (2) end up with someone else either taking care of them (rescuing) or criticizing (persecuting) them.  Individuals are in a victim role when they try to place the responsibility for their own success or failure on someone else rather than trying to solve their own problems or acting appropriately and consistently with their own abilities.”  McMahon 2005, p 423

McMahon refers to Argyris C.- theory-in-use, tied to “…social virtues such as help and support, honesty, respect of others, strength, and integrity….”  McMahon 2005, p 426

This has to be related to ToM

I call these rules – and in betrayal, these rules are broken

+++++++++++++

I cannot get stuck and frozen in the disorganized attachment place – this has to be about moving forward into time – we don’t take our early trauma emotions with us because they are not integrated (according to Liotti 2001) – all PTSD reactions, and dissociation

We are not learning – wheels are spinning, the plasticity continuum with neurotoxicity on the other end – things are heating up but it kills us because we can’t integrate

Because we cannot apply – paradox – we cannot process what is not needed by us individually or by the larger “organization” of our species – again, the details do not matter to the body – it holds onto the implicit information it can use automatically – but the factual, semantic, autobiographical, declarative, explicit – I don’t care what you refer to this process as – but we are missing the integration because the factual part of it is useless and would slow the body down

Only in an evolutionarily advanced condition would the personal self ever be an issue, and when traumas happen that early, the developing brain understands very clearly that we are in primitive, threatening, dangerous times.  This is not the time or the place to integrate – what a yuppy concept to the brain under stress – anything.  We sound like petulant children if we refuse to accept and understand these facts.

How we prevent this self-abortive process from injuring innocents – including infants and young children – IS our valid and useful concern.  When we allow traumas to perpetuate trauma in the innocent, we are sabotaging our own species’ development.

It becomes a form of socially allowable/allowed genocide.

But we must be realistic in our expectations.  We cannot expect people to integrate emotions that are overwhelming from experiences that were overwhelming – especially when they are formed into the developed brain and happened to a person well before a self was formed in the first place.

++

We speak of Theory of Mind as if it is a noun, an object, a physical thing.  Theory of Mind, as is everything connected to our brain and self, is a living process of molecular information transport and reception within the regions and circuits and networks of the brain.  When someone is brain dead, they are dead.  The rest of the time, our brain is alive and governs every aspect of our existence as living beings.

ToM is a developing process throughout the lifespan, as is attachment.  Because we are a social species, every aspect of our existence is relationship-dependent.  Life is an interconnected, relational process, as is our learning and the formation of our ever-evolving brain.

++++++++++++++++++++++

MacDonald et al 2008

There is overlap between a description of PTSD symptoms and the early manifestation of PTSD symptoms among children with disorganized attachment

This is a longitudinal study matching 78 8.5 year old children with a sample group of children born to cocaine using mothers [intrauterine cocaine exposure – IUCE] in low income population whose infant attachment patterns were studied and identified at 12 months of age

The identified insecure-disorganized pattern of insecure attachment at 12 months was very close to 20% of the population studied for both groups

Findings:  suggest quality of mother-infant relationship may be linked to differences in children’s later developing symptoms of PTSD following a traumatic event – though researchers could not distinguish the interactional effects of possible child maltreatment with children’s self-report of traumatic event exposure

Difference between the organized attachment styles:  secure,

…. insecure-avoidant-minimizing attachment behavior toward caregiver, evade physical contact, have learned that bids for affection or contact may result in rejection

….. insecure-resistant- heightening it, protect themselves through excessive self-reliance and emotionally detached play

“In contrast, children with disorganized attachment classifications appear to lack an organized strategy for coping with the stresses of the strange situation (Main & Morgan, 1996).  Instead, children exhibit behavioral disorganization or disorientation in the presence of the caregiver

….. failing to approach the caregiver when distressed

…. exhibiting contradictory behavior patterns such as seeking proximity and then freezing/stilling

…avoiding caregiver, averting gaze while at the same time maintaining contact

….exhibiting cognitive disorientation or affective dysregulation such as appearing dazed or depressed while with caregiver

…showing apprehension of caregiver on reunion

…thought to reflect approach-avoid, activation of incompatible reactions, caregiver may be seen as source of comfort and fear

…….biology may motivate distressed child to seek proximity and contact with caregiver/attachment figure, caregiver’s frightened or frightening behavior may “compel child to escape”

….caregivers of disorganized are more likely to have own histories of trauma and unresolved loss….resulting in part in feelings of helplessness

…cognitive, behavioral disorientation and dysregulation suggests these children will have difficulty in later childhood coping with even mildly stressful events

….disorganized attachment often has “deleterious long-term implications”

2 longitudinal lines of research:

+ 1 – link between disorganized attachment and dissociation (which is closely linked with PTSD symptomatology)

+ 2 – association between disorganized attachment and later externalizing behaviors

these overlap with 3 of the symptom clusters of PTSD

………….avoidance symptom cluster

……………….includes dissociative-type behaviors

…………………numbing of general responsiveness

……hyperarousal symptom cluster

………externalizing-type behaviors

…………including irritability or outbursts of anger

“Both dissociative symptoms and externalizing symptoms are responses commonly seen in individuals who have been exposed to trauma.” (3)

[no if about this] – quality of children’s early attachment relationships impact later response to trauma…..insecure-disorganized attachment (Liotti 1992, 1994) linked to subsequent vulnerability and dissociative behaviors in response to later trauma

[research shows strong link between previous dissociation and later PTSD onset]

[I do not agree with this]

“Dissociative behaviors can be seen as unconscious strategies by which some children cope with traumatic experiences (Liotti, 2004).”  (4)

[I believe dissociation is built into the brain and into the nervous system and is a physiological by-way that results from stressors to the nervous system that the brain and body have developed to cope with through dissociation.]

Carlson (1998) found adolescent dissociative symptoms were related to disorganized attachment in earlier childhood compared to children with other attachment classifications

Other researchers analyzed data from same sample (Ogawa et al, 1997) and “found that disorganized attachment in infancy was strongly associated with dissociative symptoms in adulthood.” (4)

Developmental processes underlying this relationship between disorganized attachment and later dissociative symptoms is not clearly understood

No coherent system for managing stress inherent in separations and reunion during strange paradigm

Liotti 1992 likens trancelike states to minidissociative episodes

[I think this is also too simplistic and “patronizing”]

“The behaviors may serve to help children without more advanced strategies of coping to temporarily escape from the affectively charged environments of the strange situation (Ogawa et al., 1997).” (4)

[How advanced do they think any 12 month old infant’s coping strategies can possibly be?  There is obviously something wrong with the caregivers in these situations – the 12 month infant has no capacity to have “more advanced strategies of coping” and in fact ONLY has this one strategy – escape.  These infants have been raised most likely in intolerable situations in the first place…]

[is it possible that the increased externalizing behaviors of disorganized attachment children are meant to give them a needed sense of increased control over their environment – in such a way that if later trauma happens to them, and they cannot avoid it, they will “crash” harder than normal because they were more invested in the control in the first place?  If they already perceived the world as a dangerous place, and their attempts to externally control it were all they felt they had – certainly in the absence of supportive caregiving in the first place which gave them the disorganized insecure attachment – they have less ability to access social support LATER as they did earlier – the loss becomes even more crushing]

“…transformation over the course of childhood such that the indicators of disorientation, apprehension, and helplessness seen in disorganized infants develop into controlling behaviors in early childhood….controlling style marked either by role-reversed behaviors or punitive behaviors toward the caregiver.”  Macdonald, 2008, 4

more aggressive behavior toward peers linked to history of disorganized attachment, more than with history of insecure avoidant or resistant….disorganized attachment in infancy predicts aggression in school aged children

sample of infants of mothers who had used cocaine during pregnancy, 21% showed disorganized insecure attachments – HIGH!

Predicted higher avoidance cluster PTSD symptoms and higher reexperiencing cluster PTSD after exposure to another trauma by age 8.5

Findings suggest that the quality of early dyadic relationships may be linked to differences in children’s later development of PTSD symptoms – early relational model may in part mediate children’s later traumatic stress reactions

“Children with a history of disorganized attachment may evidence particular difficulty coping with frightening situations or regulating negative affect, in part because caregivers may not have responded to their children effectively or consistently in the past.  The combination of intersecting factors contributing to some children’s inability to modulate arousal and cope with stressful events successfully may have deleterious implications for children’s  later development.  Our findings suggest that early disorganized attachment may impact the ways in which children react to later traumatic experiences.”  Macdonald, 2008, 11

Findings consistent with disorganized attachment and later psychopathology, avoidance PTSD symptom cluster related to dissociative behaviors and disorganized attachment

++++

Renaud 2008

PTSD from combat exposure

…….more disruptive effects on interpersonal and family functioning than trauma from other sources – toxic effect on marital, family, occupational functioning in comparison to other trauma experiences – true for veterans who named combat as their most upsetting life experience compared to those who did not report this — greater violence, increased risk for family-based violence and “struggles with emotional connectedness” (1) —female partners report more PTSD-like symptoms of depression, anxiety, interpersonal hostility and somatic complaints —

“There is evidence that the negative interpersonal effects of combat-related PTSD are not confined to the veterans themselves but also seep into the functioning of their intimate relationships and the families they create.”  Renaud 2008, p 1

stable social support has a protective effect against developing PTSD, is mediating factor based on quality before and after combat

history of prior trauma significantly increases risk for developing PTSD (2)

author does not include the disorganized insecure attachment category, only secure, and insecure organized — preoccupied, fearful and dismissing reflecting combinations of attachment avoidance and anxiety

Mickelson, Kessler, and Shaver (1997) reported attachment data as part of the first National Comorbidity Survey (NCS) – self-reported attachment style distribution in general population

59% secure

25% avoidant

11% ambivalent

5% unclassified

again, no mention of disorganized

Griffen and Bartholomew (1994) – participants with history of sexual abuse

42% dismissive attachment

24% secure

21% fearful

12% preoccupied

Dieperink, Leskela, Thuras, and Engdahl (2001) found in sample of former prisoners of war

65% insecure attachment — associated with lower reported PTSD severity

participants of this study, 49 male volunteers diagnosed with combat-related PTSD volunteered during Viet Nam

measured thoughts of personal incompetence, negative thoughts about the world, and personal guilt

reported history of physical abuse in childhood was associated with increased scores on all three measures

the cognitive distortion of the world being dangerous was found to have a significant contribution to attachment avoidance – also compared to general population attachment styles reflected high levels of insecure attachment, preoccupied, fearful, or dismissing (8)

“Nearly 90% of the participants endorsed attachment styles characterized by high avoidance – fearful and dismissing …less than 10% of the sample endorsed secure attachment…”  Renaud, 2008, p 8

only the cognitive distortion [this is not a distortion, it is their reality] of the world being completely dangerous contributed to attachment avoidance – both attachment anxiety and avoidance were found to contribute to the severity of PTSD symptoms

“…perception of external threat rather than perceptions of aspects of the self may be more relevant to the relationship between PTSD symptoms and attachment avoidance.”  Renaud, 2008, 9

presence of others can be inherently psychologically arousing…interaction with hyperarousal and social avoidance in trauma victims…according to Schore (1994) adult intimate relationships can provide emotional regulation influences…

Victims of interpersonal trauma have been shown to interpret ambiguous social information as a precursor to danger [see Elwood below]

Insecure attachment “…and the experience of interpersonal trauma [may] accentuate sensitivity to environmental cues related to the emotional states of others.  This heightened awareness of others appears to be related to both greater intensity of traumatic symptoms and social impairment…..A bias toward experiencing other persons as a source of danger would create a conflict with the emotional interregulating functions of attachment….Chronic states of alarm may interfere with engaging other people in effective, emotionally regulating exchanges – either by pushing others away through noxious emotional manifestations (anger, fear, lack of emotional reciprocity) or pulling away from others in the service of diminishing provocative stimuli.  This would lead to the experience of emotional connectedness as unrewarding, which Mikulincer, Shaver, and Pereg (2003) describe as the pretext for attachment-avoiding strategies geared toward deactivating the attachment system.”  Renaud, 2008, 10

This has a double negative, compounding effect – something is wrong with the social brain.  Contact with members of our species is supposed to be rewarding for us – not only is this not so, the contact is itself distressing

[we are overly sensitive to every cue in the environment – hyperaroused]

“Avoidance has several adaptive advantages for those suffering from the effects of chronic PTSD but at considerable interpersonal cost.  Attachment avoidance diminishes the reciprocal regulatory demand that comes with being attached to another person, preserving internal resources for self-soothing and self-regulating.  [neither of which we are any good at – nor have we learned that others can help us with this]  Attachment avoidance also reduces interpersonal stimuli, titrating [quantifying, measuring] the interpersonal signals that provoke hyperarousal and attachment system responses.  Finally, attachment avoidance also helps maintain the protective function of hyperarousal, by discouraging the formation of relationships that might eventually result in a diminished perception of threat from the interpersonal environment.  [For those of us with disorganized attachment this is our natural state and I do not believe it can be changed.  For people in the insecure but organized attachment classifications, perhaps this can be changed – but not easily – and with compounding traumas, becomes more and more difficult to accomplish.  This reminds me of what I wrote the other day about no goose stopping to attend to one of their own that falls out of the V – it isn’t a wise survival thing to do if threat to life is immanent.  It is also related to what I’ve written in the other manuscripts about the fundamental state of being alone in the world – that’s how we got this way in the first place, and it keeps us this way by making human contact very uncomfortable and minimally rewarding for us.  I’m not sure we have degrees of freedom of choice here….}  Although this strategy helps reduce the short-term activation of uncomfortable emotional states, in the long-term, it deprives the person of the benefits of positive social support, which can help the patient modulate the exaggerated responsiveness to external cues that result from trauma.”  Renaud, 2008, 10

++++++++++++++

Roisman, Tsai & Chiang 2004

Abstract – Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA. roisman@uiuc.edu

Attachment researchers claim that individual differences in how adults talk about their early memories reflect qualitatively distinct organizations of emotion regarding childhood experiences with caregivers. Testing this assumption, the present study examined the relationship between attachment dimensions and physiological, facial expressive, as well as self-reported emotional responses during the Adult Attachment Interview (AAI).

Consistent with theoretical predictions, more prototypically secure adults behaviorally expressed and reported experiencing emotion consistent with the valence of the childhood events they described.

Insecure adults also showed distinctive and theoretically anticipated forms of emotional response:

Dismissing participants evidenced increased electrodermal activity during the interview, a sign of emotional suppression, whereas

preoccupied adults showed reliable discrepancies between the valence of their inferred childhood experiences and their facial expressive as well as reported emotion during the AAI.

Results substantiate a case that the AAI reflects individual differences in emotion regulation that conceptually parallel observations of attachment relationships in infancy.

++++

Buchheim & Benecke 2007 –

article in German

Abstract – Klinik für Psychosomatische Medizin und Psychotherapie, Universität Ulm. anna.buchheim@uni-ulm.de

In this study we examined for the first time the

difference between patients with an anxiety disorder and healthy controls in their attachment representation and facial affective behavior during the activation of the attachment system.

13 female patients und 14 healthy women were administered with the Adult Attachment Interview (AAI). Facial affective behavior during 6 selected questions of the AAI was coded using the Emotional-Facial-Action-Coding-System (EMFACS). As expected patients with an anxiety disorder, especially panic disorders, were classified significantly more often as insecure-preoccupied with a high proportion of unresolved loss.

Against our assumption anxiety patients, independent of their attachment category, did not differ in their facial affective behavior from the control group.

A group comparison taking into account diagnosis and attachment status showed that duchenne smile (happiness) was significantly predominant in control subjects classified as secure.

Attachment security in healthy subjects, characterized by an overall valuing of positive or negative attachment experiences and coherent discourse in the AAI, was associated with positive facial affectivity.

In contrast insecure anxiety patients could be characterized by showing social smile when talking e. g. about former separation experiences from their attachment figures mostly in an incoherent manner. This could be interpreted as a self-regulating defense. Limitations of the study are the small sample size and the heterogeneous clinical group of anxiety disorders.

Ties in with facial expressions I am putting for now in well being

++++

Edelstein & Gillath 2008

Avoidant individuals limit attention to potentially distressing information, attachment avoidance was associated with emotional reduction for attachment related words in this study (e.g. intimate, loss)

These biases were strongest for those in a current romantic relationship, “suggesting that being in a close relationship may activate avoidant defensive strategies….[there was a] cognitive load, suggesting that inhibiting attention to attachment-related information requires cognitive effort.”  Abstract

Avoidance was unrelated to emotional, nonattachment-related words, demonstrating the specificity of these attentional biases….suggesting that “avoidant individuals can inhibit attention to potentially threatening information, that this ability requires cognitive effort, and that relationship status may be an important moderator of avoidant defensive strategies.”

No doubt the cognitive effort is implicit/not conscious and is part of the organized insecure pattern in that IT WORKS as a way to exert effortful control over the environment – I can see how this contributes to trauma dramas – if a person is single and their attachment system is not in full operation, they will be “off” until they get into a relationship, that fully activates their avoidant attachment system, and then the whole thing is sabotaged or blows up, or….in my dad’s case, it allowed him to ignore what happened to us and to somehow shut down or off his reactions to mother??  I will have to locate that good article from a year ago about the caregiving, attachment, etc systems…

‘Course with me, there’s the continual disorganization of approach/avoid and continual emotional upheaval of deep sorrow – drama of victim and perpetrator, etc. – can’t really do it any other way.  I cannot be in a stable relationship because I was made in and for an unstable world….it is a doom in and for and by a doomsday world

++++

Elwood et al, 2007

Information processing, interpretive biases (most studies focus on attention and memory biases) in PTSD

Processing of visual information, 40 victims, 41 non-victims of interpersonal trauma viewed a series of short positive, neutral, and threatening filmstrips of social situations with ambiguous endings, asked about their perceptions and interpretations of the situations

Victims perceived threatening situations as more predictable and more quickly increasing in risk than non-victims

Trauma status interacted

………..with the perceived predictability of positive situations

…………and the perceived speed with which neutral situations reached their conclusion to predict anxious symptoms

………and with the perceived increase in risk of positive situations to predict PTSD symptoms

This gives me a sense of scarcity, of paucity, that the PTSD people cannot afford to be generous about what might happen – the less ambiguity the better.  They say that about borderlines, that they cannot tolerate ambiguity.  Same probably with PTSD – we can eliminate it by assessing risk ASAP and in the direction of the worst case scenario – safety does not exist in our world.  We extrapolate from our past experiences that this safety is absent.  Yet all the PTSD research needs to be including a parameter to assess attachment histories – and they need to include the disorganized parameter.

++++

Oosterman & Schuengel 2007

Abstract

This study examined physiological effects of separation and reunion in a sample 3- to 6-year-old children. Using continuous ambulatory recording, changes in heart rate (HR), respiratory sinus arrhythmia (RSA), and pre-ejection period (PEP) were compared across the episodes of a separation-reunion procedure based on the strange situation. RSA decreased significantly over the course of the procedure as well as on separation from the parent and not the stranger, supporting that separation from the attachment figure elicited vagal withdrawal in young children. The absence of significant PEP effects suggest that the separation-reunion procedure, and more specifically separation from the parent, was not threatening enough to activate the sympathetic nervous system, even if children were insecure attached and inhibited with regard to strangers. Some of the variability in HR increases to reunion was explained by younger age. The findings highlight the role of the ANS as a regulatory process in the parent-child relationship.

++++

Oosterman & Schuengel 2007b

Abstract

OBJECTIVE: To determine whether foster children showed different autonomic nervous system activity on separation and reunion than control children.

………Autonomic nervous system activity in foster children was examined in relation to time in placement and disinhibited attachment. METHOD: The sample included 60 foster and 50 control children between 2 and 7 years of age who participated with their caregivers in a modified Strange Situation. Heart rate, respiratory sinus arrhythmia (RSA), and pre-ejection period were monitored continuously. Foster caregivers reported disinhibited symptoms on the Disturbances of Attachment Interview. RESULTS: The Strange Situation elicited less RSA reactivity in foster children. Differences in RSA, heart rate, and pre-ejection period responses on the specific separation and reunion episodes were not significant. RSA responses on separation from the stranger and on reunion with the foster caregiver were partly explained by time in placement and disinhibited attachment. CONCLUSIONS: Early experiences of relationship disruptions in foster children as well as short placements may have an impact on children’s adaptation to environmental and relational challenges. Stable placement may facilitate adaptive affect regulation, except for children with disinhibited symptoms. [too easy, forming attachments with everyone]

++++

Elwood et al, 2007

“Social contact promotes enhanced health and well-being, likely as a function of the social regulation of emotional responding in the face of various life stressors.”  Elwood, 2007

Yes, this is the way it is supposed to be.  But what about people in cities who don’t even look at one another?  What if we didn’t get a socialized brain in the first place?  What if we have PTSD and can’t tolerate social contact, or have an attachment disorder that makes any attachments uncomfortable if not impossible to enjoy?

“Social bonding and soothing behaviors mitigate the destructive effects of negative environmental events and promote enhanced health and well-being (Berscheid, 2003)….social isolation is now considered a major health risk (House, Landis, & Umberson, 1988).”  Elwood, 2007, 1032

married people tend on the average [is this because they are married, or because they have the ability to form a secure attachment?]  to be happier, healthier, higher marital quality is associated with decreased risk of infection, faster recovery from injury, lower rate of mortality from diagnosis of life-threatening illness

“The likely mechanism underlying these effects is the social regulation of emotional responding (Diamond, 2001; Hofer, 1984).

.security provision, distress-alleviation regulatory functions that influence negative affect and arousal (Bowlby, 1969/1982; Mikulincer, Shaver, & Pereg, 2003)

“Supportive social behaviors are known to attenuate stress-related activity in the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis (DeVries, Glasper, & Detillion, 2003).  Maternal grooming behaviors even affect glucocorticoids-receptor gene expression underlying hippocampal and HPA-axis stress reactivity in rat pups…..and I still think that human social chit chat does the same thing …

“…the neural systems supporting social affiliation are implicated in more general emotional responding.  For example, the neuropeptides oxytocin and arginine vasopressin have emerged as important mediators of social affiliation (Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005; Young & Wang, 2004), and receptors for both are found in a network of emotion-related cortical and subcortical structures in monogamous nonhuman mammals (Insel, 1997).”  Elwood, 2007, 1032

structures implicated with reward seeking implicated in maternal affection and romantic attachment in response to higher order constructs like love, friendship

….caudate-putamen

….ventral tegmentum

….portions of the dorsolateral and ventrolateral prefrontal cortex

also at same time deactivations in structures associated with regulation of negative emotion

….medial prefrontal and ventral paracingulate cortex

+++++++++++++++++++++

insert  – see in learning – mesial prefrontal cortex and nucleus accumbens

Sailer et al 2008

++++++++++++++++++++++

cue threats – distress-alleviating effects of romantic relationships on neural circuitry supporting threat responding

this study used hand-holding and threat of electric shock to investigate the social regulation of neural systems underlying response to threat [how do they know these aren’t the empathy circuits?]

results in happily married couples:

hand-holding reduces subjective unpleasantness and arousal

stranger and mate hand-holding attenuated neural threat responses, conferred a basic level of regulatory influence, in

structures implicated in modulation of affect-related action and bodily arousal

vACC –

two regions of the posterior cingulate, (visceral and musculoskeletal responses)

left supramarginal gyrus, (visceral and musculoskeletal responses)

right postcentral gyrus (visceral and musculoskeletal responses)

right DLPFC,

left caudate,

superior colliculus

neural activation to threat lower in spouse condition than no-hand condition in

vACC,

left caudate,

superior colliculus,

posterior cingulate,

left supramarginal gyrus, and

right postcentral gyrus

neural activation to threat lower in spouse condition than in stranger condition in

right DLPFC, but comparison between spouse and no-hand only approached significance

spouse hand-holding all benefits of stranger hand-holding plus regulation of emotion area

right DLPFC, caudate

emotion-related homeostatic functions – superior colliculus

“Although both spouse and stranger hand-holding resulted in lower reports of bodily arousal, only spousal hand-holding provided the additional benefit of lowering subjective reports of task-related unpleasantness.”  Coan, 2006, 1037

Both spouse and stranger hand-holding attenuated neural response to threat to some degree, but spousal hand-holding was particularly powerful…maximized in those couples with the highest quality relationship

greater activation in both the anterior insula and the hypothalamus corresponded with greater levels of subjective unpleasantness, regardless of hand-holding conditions. Coan, 2006, P 1037

………….threat-related activation in the right anterior insula, superior frontal gyrus, and hypothalamus was sensitive to marital quality.  “This suggests that individuals in higher-quality relationships benefit from greater regulatory effects on the neural systems supporting the brain’s stress response, including the affective component of pain processing (e.g. in right anterior insula….)”  Coan, 2006, 1037

“…regulation of the hypothalamus suggests that these benefits may be pervasive, as the hypothalamus influences a cascade of neurochemical regulatory processes, such as the (1037) release of corticotrophin-releasing hormone, which in turn stimulates the release of cortisol into the bloodstream – a process widely understood to hold implication for immune function and memory (Kemeny, 2003).”  Coan, 2006, 1038

important – quality of the relationship “came through” in the spousal hand-holding

…attachment relationships are “…hidden regulators – “regulators” because of the emotion-regulatory benefits attachment relationships confer, and “hidden” because those regulatory benefits are frequently apparent only when the attachment system, or one of the partners within that system, is under threat (Hofer, 1984, 1995).”  Coan, 2006, 1038

This is the potential of secure relationships – otherwise, the stressors in the insecure attachment systems keep the system activated nearly all the time, which just wears the tread off of the tires!

Social isolation as health risk, attachment relationships mitigate effects of stress, injury and infection

Why do they not note secure attachments do this – not all attachment relationships!  If they studied couples that hate one another – into trauma dramas, they might find exactly the opposite reactions!  Or would it happen even in an unhappy relationship that if the threat was bad enough the partner would respond and these effects would still be noted?  Would the threat have to be much worse for a trauma couple in order for this positive response to be noted – a sort of override of the threat that exists all the time in those relationships?  After all, all the stress they are talking about having alleviated in “marriage” is the same stress the caregivers are to protect the infants from in the first place – that gives us the ability to repeat the safe secure experience on our own as adults.

“At one level, hand-holding appears to produce a general regulatory effect on neural threat responses related to bodily attention and the coordination of motor responses; this suggests that such processes may represent the most immediate or lowest-level benefit of social soothing and support.”  Coan, 2006, 1038

“At another level, structures associated with more evaluative, attentional, and affective components of the threat response were attenuated more specifically by spousal hand-holding, which suggests that attachment figures act as emotion regulators in ways that strangers do not.  Put another way, both stranger and spousal hand-holding appear capable of decreasing the need for a coordinated bodily response to threatening stimuli, but only spousal hand-holding confers the additional benefit of decreasing the need for vigilance, evaluation, and self-regulation of affect.”  Coan, 2006, 1038

How can we have 7 billion people on this planet and still have so many lonely people? And yet if we are not comforted properly as our brain grows, we may never be able to experience these effects…they would have to expand studies like this one, and look at having one’s children with you, friends…..it’s making me feel really alone here!  And yet that is the only way I can be writing this right now……But I don’t know how people do these relationships, they seem so complicated, and yes, so terribly arousing for me….too much stimulation…too much going on, too much to attend to….I don’t think they can generalize to “people alone” without looking into WHY they are alone.  If they are alone because of early traumas (interpersonal violence, abuse and neglect) that gave them attachment disorders, it is the attachment disorder that is making them stressed and sick – a consequence of the abuse.  The being alone part is just another symptom, like the increased infections, etc.  It is much easier to look at a person and say, “They are alone” than it is to know why  this truly is so.

“Particularly promising…is the observed effect of marital quality on the hypothalamus, as links between the HPA axis and various health-related processes (e.g. immune function)….Other links are possible as well.  For example, oxytocin has been proposed as one of the mechanisms through which the positive benefits of social support are realized (Uvnaes-Moberg, 1998), and it is plausible that oxytocin activity served as a mediator of the attenuation of threat-related neural activity reported here….physical contact alone has been associated with oxytocin release from the paraventricular nuclei of the hypothalamus (Uvaes-Mober, 1998), which may in turn increase endogenous opioid activity (Uvnaes-Moberg, 1998) and target dopamine receptors related to inhibitory motor control throughout the basal ganglia (Gimpl & Fahrenholz, 2001).”  Coan, 2006, 1038

“…many of these effects should not generalize to relationships of poorer quality [discord]…”  Coan, 2006, 1038

social soothing

++++

Surget & Belzung 2008

Abstract – EA3248 Psychobiologie des émotions, Université François Rabelais Tours, UFR Sciences et Techniques, Parc Grandmont, F-37200 Tours, France.

Affective disorders comprise mood disorders such as unipolar depression and anxiety disorders, including generalized anxiety, post-traumatic stress disorder [PTSD], panic, phobia and obsessive-compulsive disorder.

The etiology of these disorders is related to stress.

Further, they are characterized by alterations of the hypothalamus-pituitary-adrenal (HPA) axis function, controlling the endocrine response to stress.

Vasopressin

is a nonapeptide that is mainly expressed and/or released

in the hypothalamus and the pituitary,

but also in other brain areas

particularly in limbic regions.

It strongly contributes to the

endocrine and neural response to stress.

Therefore, it has been suggested that vasopressin may be involved in affective disorders. Here, we review both clinical and preclinical data that investigated this hypothesis. Several studies show an increased plasmatic level of vasopressin in anxiety disorders as well as in unipolar depression.

Further, a single nucleotide polymorphism (SNP)

of the vasopressin V(1b) receptor has been found to

protect against depression.

Preclinical data are convergent with the clinical findings. For example, Brattleboro rats, that display

decreased vasopressin function, show

reduced anxiety,

reduced depressive-like behavior and

decreased HPA function.

Rats selected for

high anxiety behavior

exhibit increased HPA function

related to a SNP in the vasopressin locus

resulting in an overexpression of vasopressin.

Antagonism of the V(1b) receptor decreases anxiety and depressive-like behaviors in rodents, as well as HPA responsivity to stress. Taken together, these data indicate that

affective disorders may be related to

excessive vasopressin function

and consequently that a treatment with vasopressin receptor antagonists may be an effective treatment.

++++

Wittmann et al 2008

Abstract – 1Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria.

Stress and anxiety

are mainly regulated by amygdala and hypothalamic circuitries

involving several neurotransmitter systems and

providing physiological responses to peripheral organs

via the hypothalamic-pituitary-adrenal axis and other pathways.

The role of endogenous opioid peptides in this process is largely unknown.  [prodynorphin]

Here we show for the first time that anxiolytic parameters of explorative behavior in mice lacking prodynorphin were increased 2-4-fold in the open field, the elevated plus maze and the light-dark test. Consistent with this, treatment of wild-type mice with selective kappa-opioid receptor antagonists GNTI or norbinaltorphimine showed the same effects. Furthermore, treatment of prodynorphin knockout animals with U-50488H, a selective kappa-opioid receptor agonist, fully reversed their anxiolytic phenotype.

These behavioral data are supported by an approximal 30% reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus and central amygdala and an accompanying 30-40% decrease in corticosterone serum levels in prodynorphin knockout mice. Although stress-induced increases in corticosterone levels were attenuated in prodynorphin knockout mice, they were associated with minor increases in depression-like behavior in the tail suspension and forced swim tests. Taken together, our data suggest a

pronounced impact of endogenous prodynorphin-derived peptides on anxiety,

but not stress coping ability and

that these effects are mediated via kappa-opioid receptors.

The delay in the behavioral response to kappa-opioid receptor agonists and antagonist treatment suggests an indirect control level for the action of dynorphin, probably by modulating the expression of

CRH or neuropeptide Y,

and subsequently influencing behavior. Neuropsychopharmacology advance online publication, 17 September 2008; doi:10.1038/npp.2008.142.

++++

Bilkei-Gorzo et al 2008

Abstract – Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany. neuro@uni-bonn.de

Regulations of hormonal stress responses entail the initiation, amplitude and termination of the reaction, as well as its integration with other stress response systems. This study investigates the role of endogenous opioids in the regulation and integration of behavioral, thermal and hormonal stress responses, as these neuromodulators and their receptors are expressed in limbic structures responsible for stress responses.

For this purpose, we subjected mice with selective deletion of beta-endorphin, enkephalin or dynorphin to the zero-maze test, a mildly stressful situation, and registered behaviors and stress hormone levels. Behavioral stress reactivity was assessed using zero-maze, light-dark and startle-reactivity paradigms.

Animals lacking enkephalin displayed increased anxiety-related behavioral responses in each three,

dynorphin knockouts displayed increased anxiety– in two models, whereas the

responses of beta-endorphin knockouts indicated lower anxiety level in the zero-maze test.

All knockout strains showed marked changes in hormonal stress reactivity.

Increase in ACTH level after zero-maze test situation, unlike in wild type animals, failed to reach the level of significance in Penk1(-/-) and Pdyn(-/-) mice. Corticosterone plasma levels rapidly increased in all strains, with a lower peak response in knockouts. In wild-type and beta-endorphin-deficient mice, corticosterone levels returned to baseline within 60min after stress exposure. In contrast, mice lacking dynorphin and enkephalin showed longer-lasting elevated corticosterone levels, indicating a delayed termination of the stress reaction. Importantly, the behavioral and hormonal responses correlated in wild-type but not in knockout mice. Hyperthermia elicited by stress was reduced in animals lacking dynorphin and absent in Penk1(-/-) mice, despite of the heightened behavioral anxiety level of these strains. These results

demonstrate an important role

of the endogenous opioid system

in the integration of behavioral and

hormonal stress responses.

++++

Bilkei-Gorzo, Otto & Zimmer 2008

Abstract – Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53125 Bonn, Germany.

Enkephalin-deficient knockout mice, a genetic model of enhanced anxiety responses, and wild-type controls were housed in two separate facilities on the same campus using different caging systems.

Stress reactivity was evaluated in these animals using a zero-maze test followed by c-Fos expression analysis in limbic brain regions.

Animals with genetically or pharmacologically enhanced anxiety reared and tested in the same facility displayed similar behavioral reactivity and c-Fos induction. With same caging system

However, we found much stronger anxiety-related behavioral responses and higher c-Fos levels when animals were house in individually ventilated cages, independent of their genetic background. They don’t state their conclusions – that being housed in isolated conditions increased all their anxiety levels?  So is this a study that affirms the significance of “togetherness” or social support versus social isolation on the stress response?

++++

People might think it is inconsequential to consider attachment disorders any further than to sort people into their appropriate categories, and then go on with business as usual.  We have to realize that these attachment categories represent operating capacities for the people who are contained in them.

For example, the find that people with avoidant disorders can be completely unaware on a conscious level of the way their brain is actually processing information.  And yet researchers, with the new brain imaging technologies, can actually watch what the brain is doing with information.  What the brain is doing, say, with emotional information in an avoidant person is expending cognitive energy – under the surface, under the radar, under the level of conscious awareness – it is manipulating the conscious reality of the person in the body without their knowledge.  Is this without their permission?

Yes, mostly I would say that it is.  There are multiple dissociations going on in the brain.  If researchers want to understand how the brain is processing information, they can design experimental paradigms that dissociate one brain activity from another one.  Separate out, say, how the brain is detecting errors in incoming information from what the brain does with this information.  These kinds of dissociations or separations in processing occur in the brain without any “thousand yard stare” indication that dissociation is going on.  We need to become much more specific and knowledgeable about what dissociation is and why and how it occurs.

We by nature want to trust people.  Yet what is our “cheater detection” software?  People who are betrayed during the ages of 4-6 are placed in an impossible paradox situation where the rules that they are told they should be learning to operate correctly in the world are not the same rules that they are living in and under.  The child’s mind can still, at those ages, perform all kinds of complicated contortionistic maneuvers because the higher areas of the brain are in their growth stages.  The brain, as we know, grows in an experience-dependent fashion.  Researchers are becoming very aware of that process birth to 2, but we cannot allow ourselves to neglect that same process as it forms the higher regions of the brain, including the cortex.  This brain development continues until ages 22 – 30.  Once the brain has molded itself in any one critical brain formation stage, the individual is left to operate the rest of their lives with the structures and processes that have been established.  We need to know what happens, both to the individual and to all those that will be interacting with that person for the rest of their lives.

They are finding that people with PTSD have brain changes.  They are showing avoidant brain processing operations – which can happen in adulthood even if the early attachment history seems to have been adequate.  My guess is that if we knew what to look for “back then” in infancy, we would see that avoidant brain circuits were in fact established back then, and there they are, ready to take on the assignment later down the road of modulating overload in a trauma sufferer’s brain.  Avoidant infants have dissociations – not as recognizable as those a disorganized, disoriented infant will display, but there none the less.  Dissociation is operating in the brain, and this tendency to dissociate later is directly connected – as researchers know – with any prior history of dissociation that a person has had before a later trauma occurs.

If we are going to talk about the difference between humans an all other forms of creation, we must realize that our expanded evolution introduced the capacity for creating, implementing and understanding rules that are above and beyond those biologically established by the natural order of life.  This gives us added responsibility and vulnerability because we are not all the same.  Robins are robins, elk are elk, flowers are flowers – and not much variability exists within a species.

Humans, on the other hand, display potential for variation unlike other species at the same time that we share far more common genetic information than other species.  With humans, if something out of the ordinary happens that interferes with the “good enough” formation of our brains, we will manifest variations in our behavior, as an extension of changes in our brain formation, that will complicate life as we know it – not possible for the leaves on a tree or the petals on a flower – which will show damage due to disease and attack by external environment factors.  Humans are vulnerable INTERNALLY.

The simplest difference to detect between animal operation and humans is that only humans can lie.

++++

Panksepp 2003

++

2 ½ million years of sustained selection – Panksepp 2003, p 603

“Evolutionary biologists distinguish between proximate and ultimate or evolutionary factors in understanding inherited traits at two levels of evolutionary causality.  Proximate research deals extensively with immediate details of a mechanism (i.e., physical structure including the molecules involved, or on whole organism levels, specific circumstances that elicit behavior).  Ultimate research addresses adaptive features deduced from intergenerational and genomic mechanisms.  Both levels of causation are indispensable sides of a same coin, but, thus far, evolutionary psychology/psychiatry has largely taken us issues of ultimate causation.”  Panksepp 2003 p 604

“Much work labeled as evolutionary psychology centers on altruistic behavior and inclusive fitness.”  Panksepp 2003 p 604

“…maternal infanticide can result from a mother’s estimation of poor resources.”  Panksepp 2003 p 606

economics of lower species – “when environmental resources are scarce” mothers will kill weaker offspring to increase chance of success for survivors Panksepp 2003, 247

gee, I guess this could give me guilt for not dying!

[I think this is also tied to his discussion of neurotransmitters designed to facilitate communication about hierarchies…and in mental illness goes awry – like when mothers are competing for resources for young when they don’t have to – mother had plenty to eat!]

“chronic insecurity is likely to yield adults who have difficulties with intimacy and trust and are more likely to act out their lack of confidence by burdening others with their insecurities.”  Panksepp 2003, 247 understatement! –

“…evolution has not left the important events of birthing and the ensuing nurturance and bonding either to chance or to the vagaries of individual learning.”…many hormonal changes “heralding” birth [escalating prolactin and estradiol at birth, dropping progesterone, etc]  Panksepp, 2003 p 248

++

SIBLING COMPETITION:  “Trivers (1974) suggested parents and offspring feel different values according to their roles, which explains many sibling and parent-child conflicts.  For example, siblings commonly compete even though parents typically urge that they not; each sibling wishes to gather as many resources as possible, but the parents wish to apportion these equally, given that each child carries on an equal number of parental genes.”  Panksepp 2003 p 606

Haig 1996 – Panksepp notes:  “…some genes even within a body might compete with others, as with eye color.  Alleles with a gene from each parent express only one (dominant versus recessive).  Examining imprinted genes conferred separately from mother and father, Haig investigated facets of pregnancy and fetal growth and concluded that certain of the father’s genes seem to exploit the mother maximally for as many offspring as possible while hers work to conserve her resources to do a better job on fewer.  Even body tissue may derive from one parent instead of the other; for instance, the elements of cerebral cortex may derive more from maternally imprinted genes, while development of subcortical areas (in mice) are influenced more by paternal ones (Keverne et al., 1996).  Since subcortical areas facilitate emotional sociophysiology while cortical tissues foster more cognitive distinctions, it may be that paternal genes influence the more instinctual-emotional aspects of reproductive skills while maternal genes are more important for cognitive-economic decisions.”  Panksepp 2003 p 606

“The scientific paradigm that “selfish motives” operate in organisms and their subparts (e.g. genes) via robustly neoDarwinian selection originally arose to counter earlier ideas that individuals perform altruistically for the “good of the group.”….recent point-countering contributions, commentators suggest models by which tightly bonded groups can indeed be considered “organisms: or adaptive units, wherein altruism operates at the level of group selection (as distinct from the direct consanguinity rations that drive kinship selection); therefore self-sacrifice and altruism may merit more complex explanations (D.S. Wilson, 2002).”  Panksepp 2003 p 606

“All humans are related to one other [sic] in the sense of sharing comparable genes, but this does not prevent formation of conspecifics subgroups, alien and antagonistic to one another (Wrangham and Peterson, 1996).  For example, human laughter facilitates in- and out-group operation:  Bonding laugher cements in-group relations, but mocking (606) laughter emphasizes the rejection of alien individuals (Eibl-Eibesfeldt, 1989).  Obviously, scorn, shunning, and shame powerfully act in human emotional homeostasis and psychophysiological cascades that can promote mental distress.”  Panksepp 2003 p 607

“Psychiatric symptoms can sometimes represent proximate sociocommunicative mechanisms imprecisely deployed.  Evolutionary psychiatrists have speculated that, if an individual’s communicational mechanisms are stimulated at a time and place other than that which spawned its ultimate “design,” then the person may develop a disorder.  This relates closely to mismatch theory, which olds that mechanisms evolved for life in previous eras may not suit the present time (Bailey, 1989).  In technical terms, this may reflect an aspect of gnomic phenotypic elasticity.”  Panksepp 2003 p 607

“Over a century ago, Robertson (1990) suggested that symptoms of disease need to be traced to the functions of health, and that both need to be carried back to their origin in evolution…..How has psychiatric disorder deviated from usual sociophysiological order?”  Panksepp 2003 p 607

Bakker et al, 2002 (GAP Research Committee) – suggested concept of “the brain as an organ that manages social life”  Panksepp 2003 p 607

“Emerging cellular-molecular research on the origins of neuromodulators and neurotransmitters relates to communicational biology….The major classes of neurotransmitters originated remarkably early as intracellular messengers of unicellular organisms…Biogenic amines seem to have functioned first as intracellular signals and then acquired capacities for intercellular communication and hormonal action as well – still retaining intracellular roles.”  Panksepp 2003 p 612

“Catecholamine receptors developed from primordial muscarinic acetylcholine receptors before anthropod and chordate lineages diverged.  Dopamine probably emerged as the first but with functions limited to metabolic activity because all chordates exhibit its presence; but it probably was last to extend to neurotransmission given its location in neuronal groups higher in the neuroaxis than either norepinephrine or epinephrine.  Serotonin may have originated in chordate gut tissue (indeed 90 percent of human serotonin resides in the gut)….”  Panksepp 2003 p 612

“With vertebrate evolution, further neurotransmitter and receptor variations evolved to mediate basic sociophysiological repertoires, such as fear (clinically described as anxiety).  These appear to have elaborated further to serve conspecifics relations, as they vary with social rank hierarchies.  Serotonin and dopamine co-evolved in the course of brain [sic] as they mediated increasingly complex neuropharmacological pathways of social rank hierarchy regulation…..dopamine and serotonin work in an orchestrated fashion, often with seeming reciprocity….psychiatric disorders may represent aberrations of normal sociophysiology.”  Panksepp 2003 p 612

++++

++++

Kendall-Tackett 2007

Abstract

Inflammation is one of many risk factors for depression – physical and psychological stressors increase inflammation

………. “…an important shift in the depression paradigm:  inflammation is not simply a risk factor; it is the risk factor that underlies all the others.”

……….. “…inflammation explains why psychosocial, behavioral and physical risk factors increase the risk of depression….true for depression in general and for postpartum depression in particular.”

…….”Puerperal women are especially vulnerable to these effects because their levels of proinflammatory cytokines significantly increase during the last trimester of pregnancy – a time when they are also at high risk for depression….common experiences of new motherhood, such as sleep disturbance, postpartum pain, and past or current psychological trauma, act as stressors that cause proinflammatory cytokine levels to rise.”

“Breastfeeding has a protective effect on maternal mental health because it attenuates stress and modulates the inflammatory response….breastfeeding difficulties, such as nipple pain, can increase the risk of depression and must be addressed promptly.”

……………. “…two goals for the prevention and treatment of postpartum depression:  reducing maternal stress and reducing inflammation.  Breastfeeding and exercise reduce maternal stress and are protective of maternal mood.  In addition, most current treatments for depression are anti-inflammatory.”

Interference with “the natural order” again provides a fissure for at risk mothers and infants to fall into.  With the introduction of bottle feeding mothers such as my own were not forced into a physiological interaction with me as her infant that could perhaps have alleviated some of the complications from our birthing experience – though who knows what would have happened in my/her case if she HAD nursed me!

Interesting that the immune system provides inflammation no doubt as precaution against possible infections from birthing – with other consequences possible, especially when mothers do not breast feed – best for mothers and infants!

++++

Brunton & Russell 2008

abstract – UK

In late pregnancy maternal hypothalamo-pituitary-adrenal (HPA) axis responses to emotional and physical stressors are attenuated.

…………..This is expected to minimize the detrimental programming effects of glucocorticoid exposure on the fetuses.

We have utilized a model of immune challenge, systemic administration of interleukin-1beta (IL-1beta), to investigate the underlying mechanisms. Intravenous IL-1beta activates

corticotropin-releasing hormone (CRH)

neurones in the parvocellular division of the paraventricular nucleus (pPVN) via noradrenergic (A2 cell group) neurones in the nucleus tractus solitarii (NTS). ……………Despite comparable activation of these brainstem neurones by IL-1beta in virgin and in late pregnant rats,

……….pPVN CRH neurones are activated only in virgin rats.

As a consequence IL-1beta fails to evoke ACTH and corticosterone secretion in late pregnant rats, in contrast to virgin rats.

……….Suppressed responsiveness of the CRH neurones, and hence the HPA axis,

………….following IL-1beta in late pregnancy is explained by presynaptic inhibition of noradrenaline release in the pPVN,

………….due to increased endogenous enkephalin

…………and mu-opioid receptor production in brainstem NTS neurones.

………The factor that signals to the brain the pregnancy status of the animal and stimulates opioid production in the brainstem is allopregnanolone, a

………………………..neurosteroid metabolite of progesterone.

++++

reduced responsiveness of the HPA axis in pregnancy.

++++

Douglas et al 1998

Abstract – UK —STRESS AND PREGNANCY

Endogenous opioid regulation of neurohypophysial and hypothalamo-pituitary-adrenal (HPA) axis hormone secretion in response [stress

………… from] to forced swimming (90 s in deep water at 19 degrees C) was investigated in virgin and 21-day-pregnant rats.

…………There was no difference in basal plasma oxytocin concentrations between pregnant and virgin rats, but the opioid antagonist,

………………………naloxone,

…………increased basal oxytocin secretion in the pregnant rats.

……… Forced swimming increased oxytocin secretion similarly in pregnant and virgin rats, and this response was enhanced by naloxone.

…………….In pregnant rats naloxone had a greater effect (by 3.1-fold) than in virgins, showing stronger endogenous opioid restraint of an enhanced oxytocin secretory response to stress in pregnancy.

Vasopressin secretion was not increased with forced swimming in virgin or pregnant rats, and naloxone had no effect.

…………..ACTH and corticosterone secretion in response to forced swimming was attenuated in pregnant rats compared to virgin rats

…………Naloxone had no effect on basal plasma ACTH or corticosterone concentration, but it reduced ACTH secretion in virgin rats

………….in pregnant rats naloxone had no such effect.

……….Naloxone removed the pregnancy-related attenuation in corticosterone secretion measured at 5 min after forced swimming.

……………Fifteen minutes after forced swimming, plasma corticosterone concentrations were not different between groups.

……………In the late-pregnant rats, the increases in plasma ACTH and corticosterone induced by forced swimming were significantly prolonged compared to virgins.

The results show that endogenous opioid inhibition emerges in pregnancy to restrict the responses of oxytocin neurones to a stressor.

……………In contrast, the endogenous opioid enhancement of mechanisms regulating HPA axis secretory responses is not evident during pregnancy.

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Douglas et al 2000

Abstract – UK

Hypothalamo-pituitary-adrenal axis secretory responses to stress were compared in female virgin, late pregnant, parturient, and lactating mice.

……The basal plasma ACTH concentration was not different in pregnancy or lactation compared with virgins, but

………….corticosterone concentration and

………..corticosteroid-binding globulin capacity were greatly elevated in late pregnancy.

Secretory responses to novel environment were attenuated in pregnant,

……….but not lactating, mice compared with virgin females,

…………….whereas ACTH responses to forced swimming were attenuated in both groups.

The expression of immediate early gene (nur77) mRNA increased in paraventricular nucleus neurons after stress exposure in virgin and lactating, but not pregnant, mice.

During parturition, the basal ACTH concentration was similar to virgin and pregnant controls and did not increase with stress.

………..Oxytocin secretion in response to either novel environment or forced swimming was unchanged in any reproductive group, whereas vasopressin secretion was decreased by both stressors, but only in virgins.

………….Pretreatment with oxytocin receptor antagonist centrally had no effect on ACTH responses to stress in either virgin or pregnant mice.

………..Pretreatment with an opioid receptor antagonist increased ACTH responses to stress in virgin mice, indicating opioid inhibition, but had no effect in pregnancy.

…………Thus, in mice hypothalamo-pituitary-adrenal hyporesponsiveness in late pregnancy is a consequence of reduced responsiveness of paraventricular neurons,

………..but inhibition by opioids or intracerebral oxytocin does not appear to be involved.

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Douglas et al 2000b

Abstract – UK

In pregnancy, endogenous opioids inhibit enhanced basal and stressor-stimulated oxytocin neurone activity and secretion.

………… By contrast, stress responses of the hypothalamo-pituitary-adrenal (HPA) axis are reduced in pregnancy.

. We conclude that oestradiol and progesterone may be responsible for inducing the opioid restraint and enhanced oxytocin neurone responsiveness in pregnancy.

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Peterson, Molitor & Chao 1998

Abstract – MN

Opioids (exogenous opiates and endogenous opioid peptides) have a diversity of effects on the immune system.

………Although numerous studies have shown that opioid-induced immunosuppression can be mediated indirectly via the central nervous system (CNS) or through direct interactions with immunocytes, the precise cellular mechanisms underlying the immunomodulatory effects of opioids are largely unknown.

………..In recent years, investigations from several laboratories have indicated that opioids can operate as cytokines, the principal communication signals of the immune system.

All of the major properties of cytokines are shared by opioids,

…………. i.e., production by immune cells with paracrine, autocrine, and endocrine sites of action, functional redundancy, pleiotropy and effects that are both dose- and time-dependent.

Studies of the effects of opioids on peripheral blood mononuclear cells (PBMC) or brain cells cocultured with HIV-infected cells suggest that some of the immunoregulatory actions of opioids are mediated by ultrahigh affinity receptors on PBMC and glial cells.

……….. Because the CNS is populated predominantly by astroglia and microglia which have properties of immune cells,

………. it is possible that certain of the CNS effects of opioids involve cytokine-like interactions with glial cells.

Although there is mounting evidence supporting the concept that opioids are members of the cytokine family, the relative contribution of the opioids to immunoregulation remains unclear. The importance of opiate addiction in the AIDS epidemic means that gaining a better understanding of the mechanisms of opioid-induced immunomodulation is of more than academic interest.

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Vallejo, de Leon-Casasola & Benyamin 2004

Abstract – IL

The idea that opioids modulate the immune system is not new. By the late 19th century, Cantacuzene, used morphine to suppress cellular immunity and lower the resistance of guinea pigs to bacterial infection.

While exogenous opioids mediate immunosuppression, ……………..endogenous opiates exert opposite actions.

Acute and chronic opioid administration is known to have inhibitory effects on humoral and cellular immune responses including antibody production, natural killer cell activity, cytokine expression, and phagocytic activity. Opiates behave like cytokines, modulating the immune response by interaction with their receptors in the central nervous system and in the periphery.

Potential mechanisms by which central opiates modulate peripheral immune functions may involve both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system.

The presence of opioid receptors outside the central nervous system is increasingly recognized.

……… Those receptors have been identified not only in peripheral nerves but also in immune inflammatory cells.

………..The immunosuppression mediated by opiates may explain the increased incidence of infection in heroin addicts. Opiates may also promote immunodeficiency virus infection by decreasing the secretion of alpha and beta chemokines (important inhibitory cytokines for the expression of HIV) and at the same time increasing the expression of chemoreceptors CCR5 and CCR3, coreceptors for the virus.

The fact that peripheral immunosupression is mediated at least in part by opioid receptors located in the central nervous system ………….and that intrathecally administered opioids do not exert the same immunosuppressive effects may have important clinical implications for those patients receiving long-term opioid therapy for malignant and nonmalignant pain.

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Brunton et al 2005

Abstract – UK

Brunton PJ, Meddle SL, Ma S, Ochedalski T, Douglas AJ, Russell JA.

In late pregnant rats, the hypothalamic-pituitary-adrenal (HPA) axis is hyporesponsive to psychogenic stressors.

………….Here, we investigated attenuated HPA responses to an immune challenge and a role for endogenous opioids.

………..ACTH and corticosterone were assayed in blood samples from virgin and 21 d pregnant rats before and after endotoxin ; , interleukin-1beta, or vehicle.

……… In virgins, plasma ACTH concentrations increased 1 h after LPS and 15 min after IL-1beta, as did corticosterone, with no responses in pregnant rats.

……….. In situ hybridization revealed increased corticotrophin releasing hormone (CRH) mRNA expression in the dorsomedial parvocellular paraventricular nucleus (pPVN) and increased anterior pituitary pro-opiomelanocortin mRNA expression 4 h after IL-1beta in virgins; these responses were absent in pregnant rats.

………..In contrast, immunocytochemistry showed that Fos expression was similarly increased in the nucleus tractus solitarius (NTS) A2 region in virgin and pregnant rats 90 min and 4 h after IL-1beta.

………..Naloxone pretreatment (5 mg/kg, i.v.) restored ACTH and pPVN CRH mRNA responses after IL-1beta in pregnant rats but reduced the CRH mRNA response in virgins without affecting ACTH.

………Proenkephalin-A and mu-opioid receptor mRNA expression in the NTS was significantly increased in the pregnant rats,

……… indicating upregulated brainstem opioid mechanisms.

………… IL-1beta increased noradrenaline release in the PVN of virgin, but not pregnant, rats.

…………….However, naloxone infused directly into the PVN increased noradrenaline release after IL-1beta in pregnant rats.

Thus, the HPA axis responses to immune signals are suppressed in pregnancy at the level of pPVN CRH neurons through an opioid mechanism, possibly acting by preterminal autoinhibition of NTS projections to the pPVN.

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Zhang & Oppenheim 2005

Abstract – MD

Chemokine receptors,

………a family of Gi protein-coupled receptors responsible for cell migration,

……..are widely expressed by cells of immune and nervous systems.

Activation of receptors on the surface of leukocytes, such as opioid, vasoactive intestinal peptide, or adenosine receptors, often has inhibitory effects on chemokine receptors by a mechanism termed heterologous desensitization, resulting in suppression of immune responses.

Conversely, activation of chemokine receptors also induces heterologous desensitization of mu-opioid receptors (MOR), a class of key analgesic receptors on neurons.

………Furthermore, prior exposure of neuronal cells to chemokine treatment enhances the sensitivity of transient receptor potential vanilloid 1 (TRPV1), a heat- and ligand-gated calcium channel, which is

critical for sensing of pain.

Consequently, during inflammation, activation of chemokine receptors on neurons contributes to hyperalgesia by inhibiting MOR and concomitantly sensitizing TRPV1 via Gi protein-mediated signaling pathways.

These observations suggest that the crosstalk between chemokine receptors and neuropeptide membrane receptors serves

…………as a bridge between the immune and nervous systems.

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Holden, Jeong & Forrest 2005

Abstract – Chicago

The endogenous opioid system is one of the most studied innate pain-relieving systems.

………This system consists of widely scattered neurons that produce three opioids:

…beta-endorphin,

…the met- and leu-enkephalins,

….and the dynorphins.

These opioids act as neurotransmitters and neuromodulators at three major classes of receptors, termed mu, delta, and kappa, and produce analgesia.

Like their endogenous counterparts, the opioid drugs, or opiates, act at these same receptors to produce both analgesia and undesirable side effects. This article examines some of the recent findings about the opioid system, including interactions with other neurotransmitters, the location and existence of receptor subtypes, and how this information drives the search for better analgesics. We also consider how an understanding of the opioid system affects clinical responses to opiate administration and what the future may hold for improved pain relief. The goal of this article is to assist clinicians to develop pharmacological interventions that better meet their patient’s analgesic needs.

I suppose it was only Schore who describes how the opioid system is tied intimately with attachment patterns and human needs and fulfillment from birth

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Dreborg et al 2008

Abstract – Department of Neuroscience, Uppsala University, Box 593, SE-75124 Uppsala, Sweden.

The opioid peptides and receptors have prominent roles in pain transmission and reward mechanisms in mammals.

The evolution of the opioid receptors has so far been little studied, with only a few reports on species other than tetrapods [4 legs]. We have investigated species representing a broader range of vertebrates and found that the

four opioid receptor types (delta, kappa, mu, and NOP) are present in most of the species.

The gene relationships were deduced by using both phylogenetic analyses and chromosomal location relative to 20 neighboring gene families in databases of assembled genomes. The combined results show that the

vertebrate opioid receptor gene family arose by quadruplication of a large chromosomal block containing at least 14 other gene families.

The quadruplication seems to coincide with, and, therefore, probably resulted from, the

two proposed genome duplications

in early vertebrate evolution.

We conclude that the

quartet of opioid receptors was already present

at the origin of jawed vertebrates approximately

450 million years ago.

A few additional opioid receptor gene duplications have occurred in bony fishes. Interestingly, the

ancestral receptor gene duplications

coincide with the origin of the

four opioid peptide precursor genes. Thus, the

complete vertebrate opioid system was already established in the first jawed vertebrates.

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Bodnar 2008

Abstract – Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, 65-30 Kissena Blvd.,Flushing, NY 11367, United States.

This paper is the thirtieth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2007 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in …..pain and analgesia; …….stress and social status; …..tolerance and dependence; ……learning and memory; ….eating and drinking; ….alcohol and drugs of abuse; ….sexual activity and hormones, ….pregnancy, ….development and endocrinology; ….mental illness and mood; ……seizures and neurologic disorders; …..electrical-related activity and neurophysiology; ……general activity and locomotion; ….gastrointestinal, ….renal and hepatic functions; …..cardiovascular responses; ….respiration and thermoregulation; and ………immunological responses

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Melis et al 2004

Abstract – Bernard B Brodie Department of Neuroscience and Center of Excellence for The Neurobiology of Addictions, University of Cagliari, S.P. Sestu-Monserrato, Km 0.700, 09042 Monserrato, CA, Italy. mrmelis@unica.it

The effect of cannabinoid CB1 receptor agonists and antagonists on penile erection was studied in male rats when injected into the paraventricular nucleus of the hypothalamus. The CB1 receptor antagonist SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide] (0.5-5 microg) induced penile erection in a dose-dependent manner. The minimal effective dose was 1 microg, while the maximal response was found with 5 microg of the compound. In contrast, the CB1 receptor agonists WIN 55,212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-I,j]quinolin-6-one] (0.5-5 microg) and CP 55,940 [1alpha,2beta-(R)-5alpha]-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)cyclohexyl]phenol (0.5-5 microg) were ineffective at all the doses tested. Nevertheless, both compounds reduced the enhancing effect of SR 141716A on penile erection when given into the paraventricular nucleus at the above doses before SR 141716A. The pro-erectile effect of SR 141716A was also reduced by the non-competitive NMDA receptor antagonist dizolcipine (MK-801) (0.2 microg) and by the NO synthase inhibitor NG-nitro-l-arginine methylester (L-NAME) (20 microg) but not by the dopamine receptor antagonist cis-flupenthixol (10 microg) or the oxytocin receptor antagonist d(CH2)5Tyr(Me)2-Orn8-vasotocin (0.1 microg), when given into the paraventricular nucleus. In spite of its inability to prevent the pro-erectile effect of SR 141716A when given in the paraventricular nucleus, d(CH2)5Tyr(Me)2-Orn8-vasotocin) (1 microg) reduced almost completely SR 141716A-induced penile erection when given into the lateral ventricles. The present results show that

cannabinoid CB1 receptors

present in the paraventricular nucleus

may influence erectile function and sexual activity

by modulating paraventricular

oxytocinergic neurons mediating erectile function.

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Li & Pan 2001

Abstract – PA

The release of

….vasopressin and

…oxytocin

…from the supraoptic nucleus (SON) neurons

….is tonically regulated

….by excitatory glutamatergic

….and inhibitory GABAergic synaptic inputs.

Acetylcholine is known to excite SON neurons and to elicit vasopressin release. Cholinergic receptors are located pre- and postsynaptically in the SON, but their functional significance in the regulation of SON neurons is not fully understood. In this study, we determined the role of presynaptic cholinergic receptors in regulation of the excitatory glutamatergic inputs to the SON neurons.

The magnocellular neurons in the rat hypothalamic slices were identified microscopically, and the spontaneous miniature excitatory postsynaptic currents (mEPSCs) were recorded using the whole cell voltage-clamp technique.

These data provide new information that the excitatory effect of acetylcholine on the SON neurons is mediated, at least in part, by its effect on presynaptic glutamate release.

……Activation of presynaptic nicotinic… receptors located in the glutamatergic terminals increases the excitatory synaptic input to the SON neurons of the hypothalamus.

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Schrader & Tasker 1997

Abstract – New Orleans

The effects of activation of metabotropic glutamate receptors (mGluRs)

…..on synaptic inputs

….to magnocellular neurons

…..of the hypothalamic supraoptic nucleus (SON)

… mGluRs act to excite the somata/dendrites of presynaptic glutamatergic and GABAergic neurons. … the presynaptic somatic/dendritic receptors responsible for increased spike-dependent glutamate and gamma-aminobutyric acid (GABA) release belong to the group I mGluRs. ……… the metabotropic receptors at presynaptic glutamate and GABA terminals in the SON belong to group III mGluRs. … suggesting that presynaptic metabotropic receptors are activated by the release of endogenous glutamate.

These data indicate that mGluRs

…..in the hypothalamus

….have opposing actions at presynaptic somata/dendrites and at presynaptic terminals.

Activation of group I receptors (mGluR1 and/or mGluR5) on presynaptic somata/dendrites

…..led to an increase in spike-dependent transmitter release,

whereas activation of the group III receptors (mGluR4, 7, and/or 8) on presynaptic terminals

……suppressed glutamate and GABA release onto SON neurons.

No differences were seen in the effects of mGluR activation between immunohistochemically identified oxytocin and vasopressin neurons of the SON.

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Boudaba, Schrader & Tasker 1997

Abstract – New Orleans

We conducted whole cell voltage-clamp and current-clamp recordings in slices of rat hypothalamus to test for local excitatory synaptic circuits. Local excitatory inputs to neurons of the

….paraventricular nucleus (PVN) and

….supraoptic nucleus (SON)

The local excitatory inputs to SON and PVN neurons were mediated by glutamate release… glutamate microstimulation furnished the most direct demonstration of local excitatory synaptic circuits. Glutamate microstimulation of perinuclear sites elicited an increase in the frequency of EPSPs/EPSCs in 13% of the PVN and SON neurons tested. Two sites provided most of the local excitatory synaptic inputs to PVN neurons, the dorsomedial hypothalamus and the perifornical region.

These experiments provide converging physiological evidence for local excitatory synaptic inputs

….to hypothalamic neurons,

…..inputs that may play a role

…. in pulsatile hormone release.

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Boudaba, Di & Tasker 2003

Abstract – New Orleans

Glutamate and norepinephrine transmitter systems

……play critical roles in the synaptic control of

…..hypothalamic magnocellular neurones.

We recently reported on a norepinephrine-sensitive

……glutamate circuit within the paraventricular nucleus (PVN)

……that projects to magnocellular neurones.

Here, we present evidence for

norepinephrine regulation of glutamate release in the PVN and supraoptic nucleus (SON)

via actions on presynaptic terminals.

Whole-cell synaptic currents were recorded in magnocellular neurones of the SON and PVN in an acute slice preparation. Bath

application of norepinephrine (100 microm) caused a robust, reversible increase in the frequency of spontaneous glutamatergic excitatory postsynaptic currents in 100% of SON neurones

(246%) and in 88% of PVN magnocellular neurones (259%).

The norepinephrine-induced

…. increase in glutamate release

….was mediated by activation of both presynaptic

…alpha1 receptors and

….alpha2 receptors,

…………but the alpha1-receptor component was the predominant component of the response.

The presynaptic actions of norepinephrine were predominantly, although not completely, resistant to blockade of Na-dependent spikes, implicating a presynaptic terminal locus of action.

Interestingly, the spike-dependent component of the response

….was greater in PVN

….than in SON magnocellular neurones.

This robust presynaptic facilitation of glutamate release by norepinephrine,

…..combined with the known excitatory postsynaptic actions of norepinephrine,

…..activational effects on local glutamate circuits,

…..and inhibitory effects on gamma-aminobutyric acid release,

indicate a strong excitatory role of norepinephrine in the regulation of

oxytocin and

vasopressin

release during physiological stimulation.

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Boudaba & Tasker 2006

Abstract – Tulane U, New Orleans

Hypothalamus

Magnocellular neurons of the supraoptic nucleus (SON) and paraventricular nucleus (PVN)

….display bursting activity

…that is synchronized under certain conditions.

They receive excitatory synaptic inputs from intrahypothalamic glutamate circuits,

….some of which are activated by norepinephrine.

Ascending noradrenergic afferents and intrahypothalamic glutamate circuits may be responsible for the generation of

synchronous bursting among

oxytocin neurons and/or asynchronous bursting among

vasopressin neurons

located in the bilateral supraoptic and paraventricular nuclei.

Here, we tested whether magnocellular neurons of the PVN receive excitatory synaptic input from the contralateral PVN and the region of the retrochiasmatic SON (SONrx) via norepinephrine-sensitive internuclear glutamate circuits. … male rats, and the ipsilateral SONrx region and contralateral PVN were stimulated using electrical and chemical stimulation. Electrical and glutamate microdrop stimulation of the ipsilateral SONrx region or contralateral PVN elicited excitatory postsynaptic potentials/currents (EPSP/Cs) in PVN magnocellular neurons mediated by glutamate release, revealing internuclear glutamatergic circuits. Microdrop application of norepinephrine also elicited EPSP/Cs, suggesting that these circuits could be activated by activation of noradrenergic receptors. Repetitive electrical stimulation and drop application of norepinephrine, in some cases, elicited bursts of action potentials. Our data reveal

glutamatergic synaptic circuits

that interconnect the magnocellular nuclei

and that can be activated by norepinephrine.

These internuclear glutamatergic circuits

may provide the

functional architecture

to support burst generation and/or burst synchronization in hypothalamic magnocellular neurons

under conditions of activation.

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Smith et al 2007

Abstract –

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Endres-Becker et al 2007

Abstract – Germany

In summary, our results indicate that mu-receptor activation can inhibit the activity of TRPV1 via G(i/o) proteins and the cAMP pathway. These observations demonstrate an important new mechanism underlying the analgesic efficacy of peripherally acting mu-receptor ligands in inflammatory pain.

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Brinkman et al 1998

Abstract – IL

Opioid-induced modulation of the immune system

…………..is a complex phenomenon involving opioid receptors, central and sympathetic neural pathways, catecholamine receptors, and other regulatory mechanisms.

The precise neural pathways involved in centrally-mediated immune modulation are not currently defined. In addition,

the physiological purpose for endogenous opioid modulation of the immune system is not well understood.

Perhaps this modulation phenomenon represents an integral feedback loop within a much larger homeostatic control system.

……..Indeed, the role of the HPA axis in immune regulation can not be discarded, and in fact, probably serves to balance immune function, in concert with multiple feedback systems, around some undiscovered parameter of efficiency.   How poetic, only 10 years ago

Perhaps the physiological role of endogenous opioid control is to act as a monitor poised to subvert chronic inflammatory processes and autoimmune disorders. ………..Regardless of the evolutionary heritage of this and despite the overwhelming complexity of immune regulation, important work substantiating a

bidirectional communication link between the brain and the immune system

has created a foundation for further elucidation of the intricacies of immunoregulation.

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Molina 2005

Abstract – New Orleans

Acute injury produces an immediate activation of neuroendocrine mechanisms

…………aimed at restoring hemodynamic and metabolic counter-regulatory responses.

These counter-regulatory responses are mediated by the systemic and tissue-localized release of neuroendocrine-signaling molecules known to affect immune function. This has led to the recognition of the importance of neuroendocrine-immune modulation during acute injury as well as throughout the recovery period.

……The period immediately after acute injury is characterized by ……….upregulation of proinflammatory cytokine expression

………….leading to a later period of generalized immunosuppression.

………The course and progression of the host recovery from traumatic injury and the integrity of its response to a secondary challenge

……….is directly related to the effective control of the immediate proinflammatory responses to the initial insult.

Among the neuroendocrine mechanisms involved in restoring homeostasis,

……….the sympathetic nervous system plays a central role in mediating acute counter-regulatory stress responses to injury.

……….In addition to its recognized cardiovascular, hemodynamic, and metabolic effects, the neurotransmitters

…….released by the sympathetic nervous system

……..have been shown to affect immune function

……….through specific adrenergic receptor-mediated pathways.

In turn, cells of the immune system and their products have been shown to influence peripheral and central neurotransmission,

……….leading to the conceptualization of a

bidirectional neuroimmune communication system.

The reflex activation of this bidirectional neuroimmune pathway in response to injury,

……….integrated with the

…parasympathetic nervous system, and

…opioid and

….glucocorticoid pathways responsible for

orchestrating the counterregulatory stress response,

….results in dynamic regulation of host defense mechanisms vital for immune competence and tissue repair.

This review provides the biological framework for the integration of our understanding of the neuroendocrine mechanisms involved in mediating the stress response and their role in modulating immune function during and after traumatic injury.

The body did not start out inventing a separate pattern of defenses for humans to “deal with” psychological or emotional pain.  I do not believe separate systems exist.  Rather, when science looks closely enough at the underlying dynamics of “pathological” conditions, they will find that they are all interwoven and interconnected within our physiology in ways that will make perfect sense to us once we understand their complexities more fully.

I believe that every system in the body responds to the immune systems alert signals, including the HPA axis.  I see no reason, yet anyway, to believe, personally, that the HPA axis is the “head” of the program.  It exists, I suspect, as an appendage to the immune system which has itself evolved from the level of single-cell protection abilities into the complex system used by mammals to accomplish the same job – keep the organism safe at all costs.  Healing is the same process – we live in a body, and whatever is “wrong” with us is IN our body!

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Molina 2006

Abstract – New Orleans

Traumatic injury, surgical interventions and sepsis are amongst some of the clinical conditions that result in

…….marked activation of neuroendocrine and opiate responses aimed at restoring haemodynamic and metabolic homeostasis.   Read here, I believe, same for “psychological” traumatic injury

The central activation of the neuroendocrine and opiate systems,

……………known collectively as the stress response,

is elicited by diverse physical stressor conditions, including ischaemia, glucopenia and inflammation.

The role of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system in counterregulation of haemodynamic and metabolic alterations has been studied extensively.

…………..However, that of the endogenous opiates/opioid system is still unclear.

………… In addition to activation of the opiate receptor through the endogenous release of opioids,

…………pharmacotherapy with opiate receptor agonists is frequently used for sedation and analgesia of injured, septic and critically ill patients.

………… How this affects the haemodynamic, cardiovascular, metabolic and immune responses is poorly understood.

The variety of opiate receptor types, their specificity and ubiquitous location both in the central nervous system and in the periphery adds additional complicating factors to the clear understanding of

their contribution to the stress response to the various physical perturbations.

This review aims at discussing scientific evidence gathered from preclinical studies on the role of endogenous opioids as well as those administered as pharmacological agents on the host cardiovascular, neuroendocrine, metabolic and immune response mechanisms critical for survival from injury ….

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Stefano et al 1996

Abstract – NY

The discovery of the ability of the nervous system to communicate through “public” circuits with other systems of the body is attributed to Ernst and Berta Scharrer, who described the neurosecretory process in 1928. Indeed, the immune system has been identified as another important neuroendocrine target tissue.

Opioid peptides are involved in this communication (i.e., neuroimmune) and with that of autoimmunoregulation (communication between immunocytes).

The significance of opioid neuropeptide involvement with the immune system is ascertained from the presence of novel delta, mu, and kappa receptors on inflammatory cells that result in modulation of cellular activity after activation, as well as the presence of specific enzymatic degradation and regulation processes.

In contrast to the relatively uniform antinociceptive action of opiate and opioid signal molecules in neural tissues,

……… the presence of naturally occurring morphine in plasma and a novel mu3, opiate-specific receptor on inflammatory cells adds to the growing knowledge that opioid and opiate signal molecules may have antagonistic actions in select tissues.

……………In examining various disorders (e.g., human immunodeficiency virus, substance abuse, parasitism, and the diffuse inflammatory response associated with surgery) evidence has also been found for the involvement of opiate/opioid signaling in prominent mechanisms.

…………In addition, the presence of similar mechanisms in man and organisms 500 million years divergent in evolution bespeaks the importance of this family of signal molecules.

The present review provides an overview of recent advances in the field of opiate and opioid immunoregulatory processes and speculates as to their significance in diverse biological systems.

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Molina 2001

Abstract – New Orleans

The aim of the present study was to examine the role of opiate receptor activation in modulating the hemodynamic, neuroendocrine, and tissue (lung and spleen) cytokine responses to fixed pressure (40 mm Hg) hemorrhage. Chronically catheterized, conscious unrestrained non-heparinized male Sprague-Dawley rats were pretreated with either naltrexone (15 mg/kg intraperitoneally in 0.5 mL of saline) or saline (0.5 mL) 15 min prior to hemorrhage followed by fluid resuscitation with Ringer’s lactate. Animals were sacrificed at completion of the 60-min resuscitation period. Blood loss required to achieve mean arterial blood pressure (MABP) of 40 mm Hg was higher in naltrexone-treated animals than in time-matched saline controls (4.4+/-0.2 versus 3.7+/-0.2 mL/100 g BW, P< 0.05). Hemorrhage increased plasma levels of corticosterone (30%) and ACTH (3-fold) within 15 min. Naltrexone prevented the hemorrhage-induced rise in corticosterone without affecting the rise in ACTH. Hemorrhage increased beta-endorphin levels (4-fold) and produced an immediate (5 min) and progressive increase in circulating epinephrine and norepinephrine levels reaching values that were 50- and 20-fold, respectively, higher than basal.

Pre-treatment with naltrexone did not alter the time course or magnitude of the hemorrhage-induced increases in plasma beta-endorphin or catecholamines. Hemorrhage increased lung and spleen content of TNF (60%), IL-1alpha (300%), IL-6 (40%-60%), and IL-10 (80%) above values of time-matched sham control animals. Pre-treatment with naltrexone blunted the magnitude of the increases in tissue cytokine content in response to a given blood loss. These results indicate that

endogenous opiates modulate the hemodynamic instability, neuroendocrine, and cytokine responses to hemorrhagic shock.

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Molina 2001b

Abstract – New Orleans

The early stress responses to hemorrhagic shock, trauma and endotoxicosis are associated with an early proinflammatory response characterized by

…..increased gene expression of proinflammatory cytokines,

…..PMN influx and accumulation in the lung and apoptosis.

The central role of the neuroendocrine system in modulating these proinflammatory responses has been strongly suggested by recent studies.

OBJECTIVES: To examine the role of noradrenergic innervation in modulating the early increase in lung and spleen content of TNF-alpha in response to fixed-pressure (40 mm Hg) hemorrhage in vivo. METHODS: Conscious unrestrained nonheparinized male Sprague-Dawley rats (n = 42) were randomized to receive intraperitoneally either 6-hydroxy-dopamine (6-OHDA; chemical sympathectomy, SNSx) or saline (0.3 ml) prior to undergoing hemorrhage followed by fluid resuscitation with lactated Ringer’s solution. Animals were sacrificed at completion of the resuscitation period and tissue samples (lung and spleen) excised for determination of TNF-alpha content, myeloperoxidase activity and apoptosis.

RESULTS: Hemorrhage resulted in an immediate marked elevation in circulating epinephrine and norepinephrine levels (10- and 2-fold, respectively), increasing their plasma ratio to 6:1.

…….SNSx depleted tissue stores of norepinephrine (80%), did not alter basal plasma levels of epi- or norepinephrine or the hemorrhage-induced rise in epinephrine, but completely prevented the rise in circulating norepinephrine. Hemorrhage increased lung and spleen contents of TNF-alpha (55 and 72%, respectively). SNSx significantly enhanced the hemorrhage-induced rise in lung TNF in response to hemorrhage. CONCLUSIONS: These results show a suppressive role for noradrenergic innervation on the hemorrhage-induced increase in tissue TNF-alpha content in vivo.

We speculate that the effects of norepinephrine

….. are protective from tissue injury

……but are likely to contribute to the generalized immunosuppression following trauma.

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Molina 2002

Abstract – New Orleans

1. The haemodynamic and cardiovascular responses to stress,

….. in addition to being under control of the autonomic nervous system,

….are also under opiate modulation.

Our studies have provided evidence for activation of the endogenous opioid system in haemorrhagic shock, sepsis and trauma.

Furthermore, we have demonstrated that both central and systemic opiate administration to naïve rats result in marked alterations in haemodynamic responses, which are associated with activation of the sympathetic nervous system.

2. Because of the ubiquitous presence of opiate receptors

….in both the central nervous system and peripheral tissues,

…..as well as their production and release centrally and peripherally,

…..this facilitates an endocrine as well as a paracrine contribution to modulating vascular responses to stress, either directly or indirectly.

Results from previous studies suggest that endogenous opioids are not involved in mediating the lipopolysacharide-induced hypotensive response.

3. In more recent studies, we have examined the role of opiate receptor activation in modulating the haemodynamic and neuroendocrine responses to fixed pressure haemorrhagic shock in conscious unrestrained rats. Using systemic opiate blockade (naltrexone, 15 mg/kg, i.p.) prior to haemorrhage, we have observed that blood loss required to achieve mean arterial blood pressure of 40 mmHg was higher in naltrexone-treated animals than in time-matched saline controls. Interestingly, the haemodynamic modulation exerted by naltrexone cannot be attributed to differences in circulating catecholamine levels. Haemorrhage produced an immediate and progressive increase in circulating adrenaline and noradrenaline levels,

…..reaching values that were 50- and 20-fold higher than basal, respectively.

Naltrexone pretreatment did not alter the time-course or magnitude of the rise in circulating levels of catecholamines.

4. These results indicate that endogenous opioid activation contributes to the haemodynamic dishomeostasis associated with blood loss.

Tears are the blood of our hearts – this system regulates both blood and tears!

Our findings suggest

…..stress-specific roles for opiate-sensitive haemodynamic counter-regulatory responses.

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Jiang 2008

Abstract – China – need this article

Stress or neuroendocrine response [stress, then, is quite actually a neuroendocrine response to trauma]

……..usually occurs soon after trauma,

…..which is central to the maintenance of post-traumatic homeostasis.

Immune inflammatory response has been recognized to be a key element both in the pathogenesis of post-traumatic complications and in tissue repair.

Despite the existence of multiple and intricate interconnected neuroendocrine pathways, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system have been considered to be the most important in trauma.

Although the short-term and appropriate activation of these stress responses is vital to the host’s adaptation, prolonged duration and exaggerative magnitude of their activity leads to deleterious effects on immune function in trauma, causing immune dissonance.

The overall appropriate and controlled activation and termination

…………of the neuroendocrine responses that mediate the necessary physiological functions involved in maintaining and restoring homeostasis in the event of trauma are of critical importance.

This review will describe the effects of some important neuroendocrine responses on immune system. Present evidences indicate that the

neuroendocrine and immune systems form a cohesive and integrated early host response to trauma,

and identify areas for further research to fully elucidate the regulatory role of neuroendocrine system in trauma.

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Swaab, Bao & Lucassen 2005

Abstract – The Netherlands

Corticotropin-releasing hormone (CRH) plays a central role

in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response.

The action of CRH on ACTH release is

…..strongly potentiated by vasopressin,

that is co-produced in increasing amounts when the hypothalamic paraventricular neurons are chronically activated.

Whereas vasopressin stimulates ACTH release in humans, oxytocin inhibits it.

ACTH release results in the release of corticosteroids from the adrenal

that, subsequently, through mineralocorticoid [MR] and glucocorticoid [GR] receptors,

………exert negative feedback on, among other things, the

hippocampus, the

pituitary and the

hypothalamus.

The most important glucocorticoid in humans is

…cortisol,

…. present in higher levels in women than in men.

During aging, the activation of the CRH neurons is modest compared to the extra activation observed in Alzheimer’s disease (AD) and the even stronger increase in major depression.

CRH neurons increasingly activated in depression

The HPA-axis is hyperactive in depression,

………due to genetic factors

……..or due to aversive stimuli that may occur during early development or adult life.

At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression.

…………Increased production of vasopressin in depression [also tied to higher anxiety trait – genetic] does not only occur in neurons that colocalize CRH, but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin,

…..that have been related to an enhanced suicide risk.   DOVES

The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression.

The suprachiasmatic nucleus (SCN), i.e.,

……the biological clock of the brain,

………shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation.

OK, here again there’s a contradiction – both high and low vasopressin in depression?  Here’s one of my connections to the biological clock – how am I supposed to be able to see the bigger picture here because I KNOW there is one, that all these reactions are connected!

The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. ……….These hypothalamic peptidergic systems, i.e.,

…the HPA-axis,

… the suprachiasmatic nucleus (SCN),,

…the supraoptic nucleus (SON) and

…the hypothalamo-pituitary thyroid (HPT)-axis,

have many interactions with aminergic systems that are also implicated in depression. CRH neurons are strongly activated in depressed patients, and so is their HPA-axis, at all levels,

…………but the individual variability is large.

It is hypothesized that particularly

a subgroup of CRH neurons that projects into the brain is activated in depression and induces the symptoms of this disorder.

On the other hand, there is also a lot of evidence for a direct involvement of glucocorticoids in the etiology and symptoms of depression.

Although there is a close association between cerebrospinal fluid (CSF) levels of CRH and alterations in the HPA-axis in depression, much of the CRH in CSF is likely to be derived from sources other than the PVN.

………..Furthermore, a close interaction between the HPA-axis and the hypothalamic-pituitary-gonadal (HPG)-axis exists.

Organizing effects during fetal life as well as activating effects of sex hormones on the HPA-axis have been reported.

…..Such mechanisms may be a basis for the higher prevalence of mood disorders in women as compared to men.

…..In addition, the stress system is affected by changing levels of sex hormones, as found, e.g., in the premenstrual period, ante- and postpartum, during the transition phase to the menopause and during the use of oral contraceptives. In depressed women, plasma levels of estrogen are usually lower and plasma levels of androgens are increased, while testosterone levels are decreased in depressed men.

This is explained by the fact that both in depressed males and females the HPA-axis is increased in activity, parallel to a diminished HPG-axis, while the major source of androgens in women is the adrenal, whereas in men it is the testes.

……. It is speculated, however, that in the etiology of depression the relative levels of sex hormones play a more important role than their absolute levels. Sex hormone replacement therapy indeed seems to improve mood in elderly people and AD patients.

Studies of rats have shown that high levels of cumulative corticosteroid exposure and rather extreme chronic stress induce neuronal damage that selectively affects hippocampal structure.

Studies performed under less extreme circumstances have so far provided conflicting data. The corticosteroid neurotoxicity hypothesis that evolved as a result of these initial observations is, however, not supported by clinical and experimental observations.

In a few recent postmortem studies in patients treated with corticosteroids and patients who had been seriously and chronically depressed no indications for AD neuropathology, massive cell loss, or loss of plasticity could be found, while the incidence of apoptosis was extremely rare and only seen outside regions expected to be at risk for steroid overexposure.

In addition, various recent experimental studies using good stereological methods failed to find massive cell loss in the hippocampus following exposure to stress or steroids, but rather showed adaptive and reversible changes in structural parameters after stress.

. Although cortisol and CRH may well be causally involved in the signs and symptoms of depression, there is so far no evidence for any major irreversible damage in the human hippocampus in this disorder.

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Keck 2006

Abstract – Division of Psychiatry Research, University Hospital of Psychiatry Zurich, Zurich, Switzerland. martin.keck@puk.zh.ch

Affective disorders tend to be chronic and life-threatening diseases: suicide is estimated to be the cause of death in 10-15% of individuals with major depressive disorders.

Major depression is one of the most prevalent and costly brain diseases with up to 20% of the worldwide population suffering from moderate to severe forms of the disease.

Only 50% of individuals

with depression show full remission

in response to currently available antidepressant drug therapies

which are based on serendipitous discoveries made in the 1950s. Previously underestimated, other severe depression-associated deleterious health-related effects have increasingly been recognized. Epidemiological studies have provided substantial evidence that

patients with depression have a 2-4-fold increased risk both of developing cardiovascular disease and of mortality after experiencing a myocardial infarction. Cannabinoid system problems here?

The majority of patients suffering from affective disorders have measurable shifts in their stress hormone regulation as reflected by elevated secretion of central and peripheral stress hormones or by altered hormonal responses to neuroendocrine challenge tests. In recent years, these alterations have increasingly been translated into testable hypotheses addressing the pathogenesis of illness. Refined molecular technologies and the creation of genetically engineered mice have allowed to

specifically target individual genes involved in regulation of corticotropin releasing factor (CRF) and vasopressin (AVP) system elements.

The cumulative evidence makes a strong case implicating dysfunction of these systems in the etiology and pathogenesis of depression and pathological anxiety.

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Hauger et al 2006

Abstract – San Diego VA Healthcare System, University of California San Diego, La Jolla, 929093-0603, USA. rhauger@ucsd.edu

Corticotropin-releasing factor (CRF)

and the related urocortin peptides

mediate

behavioral,

cognitive,

autonomic,

neuroendocrine and

immunologic responses to aversive stimuli

by activating CRF(1) or CRF(2) receptors

in the central nervous system and anterior pituitary.

Markers of hyperactive central CRF systems, including CRF hypersecretion and abnormal hypothalamic-pituitary-adrenal axis functioning, have been identified in subpopulations of patients with anxiety, stress and depressive disorders. Because CRF receptors are rapidly desensitized in the presence of high agonist concentrations, CRF hypersecretion alone may be insufficient to account for the enhanced CRF neurotransmission observed in these patients. Concomitant dysregulation of mechanisms stringently controlling magnitude and duration of CRF receptor signaling also may contribute to this phenomenon. While it is well established that the

CRF(1) receptor mediates

many anxiety- and depression-like behaviors

as well as HPA axis stress responses,

CRF(2) receptor functions are not well understood at present. One hypothesis holds that

……CRF(1) receptor activation initiates fear and anxiety-like responses, ….while CRF(2) receptor activation re-establishes homeostasis by counteracting the aversive effects of CRF(1) receptor signaling.

An alternative hypothesis posits that

….CRF(1) and CRF(2) receptors contribute to opposite defensive modes, with …CRF(1) receptors mediating

active defensive responses triggered by escapable stressors, and

….CRF(2) receptors mediating anxiety- and depression-like responses induced by inescapable, uncontrollable stressors.

CRF(1) receptor antagonists are being developed as novel treatments for affective and stress disorders. If it is confirmed that the CRF(2) receptor contributes importantly to anxiety and depression, the development of small molecule CRF(2) receptor antagonists would be therapeutically useful.

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Russel & Brunton 2006

Abstract – UK

In late pregnant rats neuroendocrine stress responses, expressed as increased oxytocin secretion and activation of the hypothalamo-pituitary-adrenal axis, are attenuated.

………..These adaptations preserve the oxytocin store for parturition and prevent pre-term birth, and protect the fetuses from adverse programming by exposure to excess glucocorticoid.

………..Mechanisms of adaptations for oxytocin neurones are reviewed, using challenge with systemic interleukin-1beta, simulating activation of immune signaling by infection, as a stressor of special relevance in pregnancy.

In virgin rats, systemic interleukin-1beta stimulates the firing of oxytocin neurones, and hence oxytocin secretion,

……………. but interleukin-1beta has no effects in late pregnant rats.

………….This lack of response is reversed by naloxone treatment just before interleukin-1beta administration, indicating endogenous opioid suppression of oxytocin responses in late pregnancy.

…………..This opioid presynaptically inhibits noradrenergic terminals impinging on oxytocin neurones.

……………. Finasteride pretreatment, inhibiting progesterone conversion to allopregnanolone, a positive GABA(A) receptor allosteric modifier, also restores an oxytocin response to interleukin-1beta.

……………This finasteride effect is reversed by allopregnanolone treatment.

In virgin rats allopregnanolone attenuates the oxytocin response to interleukin-1beta, which is exaggerated by naloxone. The effects of naloxone and finasteride in late pregnant rats in restoring an oxytocin response to interleukin-1beta are not additive.

…………Accordingly, allopregnanolone may both enhance GABA inhibition of oxytocin neurone responses to interleukin-1beta, and induce opioid suppression of noradrenaline release onto oxytocin neurones.

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Wigger & Neumann 2002

Abstract – Germany

Oxytocin secretion into blood in response to swim stress is differentially regulated by endogenous opioids in virgin and pregnant rats.

………..Here, the influence of endogenous opioids on oxytocin release within the hypothalamic paraventricular and supraoptic nuclei was investigated using microdialysis in virgin and pregnant (day 19-21) rats. Rats … were injected with naloxone … or vehicle (sterile saline) and, 3 min later, were forced to swim (10 min at 19 degrees C).

……….Within the paraventricular nucleus, basal and stimulated oxytocin release did not significantly differ between vehicle-treated virgin and pregnant rats.

……….After naloxone, local oxytocin release in response to swimming was lowered in virgin rats (P<0.01), whereas it was further increased in pregnant rats (P<0.01).

…………Within the supraoptic nucleus, basal oxytocin release was significantly lower in pregnant compared to virgin rats (P<0.01).

………Forced swimming induced a similar rise in intranuclear oxytocin release in both vehicle-treated virgin and pregnant rats, but peak levels were still higher in the virgin controls.

………… In contrast to the paraventricular nucleus, naloxone did not alter swim-induced oxytocin release within the supraoptic nucleus either in virgin or pregnant rats.

………Vasopressin release in the paraventricular nucleus was also increased by forced swimming but there was no effect of pregnancy or naloxone on it.

In summary, in pregnancy, basal and stress-induced oxytocin release within the paraventricular nucleus was not changed, whereas it was blunted within the supraoptic nucleus.

………. Further, within the paraventricular nucleus the excitatory effect of endogenous opioids on local oxytocin release seen in virgins

………………..was switched into an inhibitory action in pregnancy.

……………In contrast, endogenous opioids were evidently not involved in the regulation of swim-induced oxytocin release within the supraoptic nucleus either in virgin or pregnant rats.

Thus, pregnancy-related neuroendocrine plasticity also includes site-specific functional alterations in opioid receptor-mediated actions in the hypothalamus.

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Douglas et al 2005

Abstract – UK

We investigated whether

changes in noradrenaline neurotransmission in the hypothalamus

could explain the hyporesponsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in late pregnancy.

…………Noradrenaline release within the hypothalamic paraventricular nucleus in response to swim stress… was lower in 20-day pregnant rats compared to virgin rats.

…………Driving a central noradrenergic pathway using intravenous cholecystokinin increased adrenocorticotropic hormone (ACTH) secretion in virgin rats, but the response was significantly less in 16-day and 20-day pregnant rats.

………..Thus, the activity of noradrenergic inputs to the paraventricular nucleus and the HPA axis is attenuated in late pregnancy.

The sensitivity of the HPA axis to noradrenaline in pregnancy was investigated by intracerebroventricular administration of an alpha1-receptor antagonist, benoxathian, before and during exposure to swim stress.

……….. In virgin rats, benoxathian increased basal and stress-induced ACTH secretion, but in late pregnant rats the benoxathian effects were attenuated, indicating

……….reduced sensitivity of the HPA axis to noradrenaline neurotransmission and/or the inability of the system to become disinhibited at this time.

alpha1A-adrenoreceptor mRNA expression in the parvocellular and magnocellular paraventricular nucleus…was decreased in late pregnant compared to virgin rats.

……………Additionally, blocking endogenous opioid inhibition with naloxone pretreatment restored the ACTH secretory response to cholecystokinin in pregnant rats. Thus,

…………. in late pregnancy, there is reduced noradrenergic input to the paraventricular nucleus and reduced alpha1A-receptor expression in the paraventricular nucleus, both of which may contribute to the

………….reduced responsiveness of the HPA axis in pregnancy.

++++++++++++++++++

MOTHERS AND INFANTS

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Fish et al 2004

Abstract – Montreal

Early life experiences shape an individual’s physical and mental health across the lifespan.

Not surprisingly, an upbringing that is associated with adversity can produce detrimental effects on health.

A central theme that arises from studies in human and nonhuman species is that the effects of adversity are mediated by the interactions between a mother and her young.

In this review we describe some of the long-term effects of maternal care on the offspring and we focus on the impact of naturally occurring variations in the behavior of female rats.

…………Of particular interest are mothers that engage in high or low amounts of licking/grooming (LG) and arched-back nursing (ABN) of their pups, but do so within the normal range for this species.

………Such variations in LG-ABN

………… can alter the function of the hypothalamic-pituitary-adrenal (HPA) axis,

……….and cognitive and emotional development by directly affecting the underlying neural mechanisms.

At the heart of these mechanisms is gene expression.

By studying the hippocampal glucocorticoid receptor gene, we have identified

…………that maternal care regulates its expression by changing two processes: the acetylation of histones H3-K9, and the methylation of the NGFI-A consensus sequence on the exon 1(7) promoter.

Sustained “maternal effects” appear elsewhere in biology, including plants, insects, and lizards, and may have

……………evolved to program advantages in the environments that the offspring will likely face as adults.

This also works the other way around to program us for DISADVANTAGES IN THE ENVIRONMENT THAT WE ARE LIKELY TO FACE

Given the importance of early life and parent-child interactions to later behavior, prevention and intervention programs should target this critical phase of development.

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Walker et al 2004

Abstract – Montreal

Optimal early development in most species is dependent upon a stable relationship between the mother and her infant.

…………The research described here focuses on the reciprocal nature of this dyad in rodents and humans, with respect to the regulation of responsiveness to stress in both mother and offspring.

Dietary influences are critical not only to regulate infant growth but also to modulate the response of the neuroendocrine system to stress and, possibly, to influence some aspects of brain development.

See Schore on stress and nutritional environment of developing brain

In particular, we discuss the role of leptin, a protein produced in the adipose tissue and present in

maternal milk,

………….that reduces responses to stress in the infant.

…………We suggest that leptin acts on both central (hypothalamus and hippocampus) and peripheral (pituitary, adrenal gland) targets in the infant to reduce exposure to glucocorticoids and enhance hippocampal development during a sensitive period of brain development.

There is also evidence to support the reverse regulatory influence, in which maternal state is profoundly affected by stimulation from the young.

During the period of lactation, mothers exhibit lower neuroendocrine and behavioural responses to several types of stressors, except possibly those representing a threat to the infant.

………….This ability to “filter” relevant from irrelevant stimuli while caring for their young might be viewed as adaptive for the mother-infant dyad,

……………..and the inability to filter adequately stressful stimuli could at least in part be associated with the development of postpartum depression.

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Francis & Meaney 1999

Abstract – Montreal

Studies dating from the 1950s have documented the impact of early life events on the development of behavioral and endocrine responses to stress.

……….Recent findings suggest that these effects are mediated through changes in mother-offspring interactions and have identified central corticotropin-releasing factor systems as a critical target for the effects of variations in maternal care.

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Tu, Lupien & Walker 2006

Abstract – Montreal

Rat studies show that hypothalamic-pituitary-adrenal (HPA) responsiveness to physical and emotional stressors is attenuated during lactation,

……….although situations evoking pup endangerment can supersede this phenomenon.

Notice the word can – in humans certainly does not always occur

In the human population, blunted cortisol responses are seen in primiparous [first time mothers] breastfeeding compared to bottlefeeding mothers following physical stress, but not after psychosocial stress.

It is currently unknown whether stressor salience (child-related versus nonrelated stressor) has a differential effect on cortisol reactivity as a function of infant feeding choice and whether HPA responses to stress could be modified by parity.

We investigated the impact of infant feeding type and maternal parity on salivary cortisol and alpha-amylase response to stress in 5-20-week postpartum mothers using exposure to the Trier Social Stress Test (TSST) and to an emotional film evoking threats to a child.

……….Analyses show that alpha-amylase responses were similar in all groups and for both types of stress, suggesting that sympathetic reactivity was independent of infant feeding type and parity.

…………By contrast, cortisol response was affected by these variables.

………….In primiparous mothers, cortisol reactivity to psychological stressors did not vary as a function of infant feeding type while, among multiparous mothers, breastfeeding was associated with reduced responsiveness to the TSST and child-related stressor.

………….. We speculate that changes in neural mechanisms occurring as a result of pregnancy and lactation and that modulate the HPA axis in women might be exacerbated with multiple repeats of the pregnancy/lactation period.

This would serve to ‘desensitize’ stress circuits and reduce the overall stress-induced cortisol secretion after multiple births.

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Heinrichs et al 2001

Abstract – Germany

In several studies lactation has been shown to be associated with a hypothalamic-pituitary-adrenal axis hyporesponsiveness to physical and psychological stressors.

As it is not known whether the marked blunting of endocrine stress reactivity in women can be ascribed to suckling as a short-term effect or to lactation in general, the acute effects of suckling on the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary system responses to mental stress were investigated in lactating women.

………… Forty-three lactating women were randomly assigned either to breast-feed or to hold their infants for a 15-min period with the onset 30 min before they were exposed to a brief psychosocial stressor (Trier Social Stress Test).

……………. Both breast-feeding and holding the infant yielded significant decreases in ACTH, total plasma cortisol, and salivary free cortisol

……….There were no significant differences in baseline hormone levels between the groups 1 min before the stress test. In response to stress exposure, ACTH, total plasma cortisol, salivary free cortisol, norepinephrine, and epinephrine were significantly increased in all lactating women

……… However, total cortisol and free cortisol responses to stress were attenuated in breast-feeding women who also showed significantly decreasing PRL levels during the stress test

……….In addition, there was no change in plasma oxytocin or vasopressin in response to the stressor. Breast-feeding as well as holding led to decreased anxiety whereas, in contrast, stress exposure worsened mood, calmness, and anxiety in the total group

From these data we conclude that lactation in women, in contrast to that in rats, does not result in a general restraint of the hypothalamic-pituitary-adrenal axis response to a psychosocial stressor.

……..Rather, suckling is suggested to exert a short-term suppression of the cortisol response to mental stress.

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Wilson et al 2005

Abstract – GA

Chronic stress can have a deleterious effect on the re-productive axis that, for females, is manifested in an increased incidence of infertility.

This makes sense – if an environment is malevolent and creates stress, there are not good conditions for reproducing, not enough for the offspring, wait until the stress goes down because that means the environment is better

However, gonadal steroids may, in turn, affect a female’s response to stress as measured by activity within the

limbic-hypothalamic-pituitary-adrenal (LHPA) axis.

What is not clear is whether a history of exposure to stress modifies the effect of gonadal steroids on LHPA responsivity. Rhesus monkeys present a unique opportunity to assess LHPA responsivity when housed socially in groups. Under these situations, monkeys exhibit a rich network of affiliation and have established social status hierarchies.

Previous work indicates that socially subordinate macaque females are hypercortisolemic due to

……………diminished gluco-corticoid negative feedback.

Uh-Oh!  They have a psychopathological condition?

The present study tested the hypothesis that estradiol (E2) would decrease gluco-corticoid negative feedback, assessed from a dexamethasone (DEX) suppression test, and increase the response to corticotropin releasing factor (CRF) and that these effects would be attenuated by co-treatment with P4. In addition,

………….we also determined whether E2 and P4 would differentially affect LHPA responsiveness to pharmacological challenge in socially dominant compared with subordinate females.

…………Endogenous gonadal hormone secretion in female rhesus monkeys (n = 7) was suppressed by continuous treatment with a sustained release formulation of the GnRH analog leuprolide acetate (Lupron Depot).

………..The response to a combined DEX suppression-CRF stimulation test was assessed using a counterbalanced design during a placebo (control) treatment condition and during E2, P4, and E2 + P4 re-placement therapy.

Females who were members of a large breeding group of 140 adults and juveniles of both sexes, were classified as dominant (n = 4) or subordinate (n = 3) based on the relative social dominance positions within the group. Plasma levels of cortisol were significantly higher during E2 replacement compared to the other treatment conditions following DEX suppression and stimulation with CRF.

For which females?

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Neumann, Kromer & Bosch 2005

Abstract – Germany

The neuroendocrine consequences of repeated exposure of the pregnant mother to relevant stressors have been studied in the offspring, but not in the mothers. As these stress effects might depend on the genetically determined stress susceptibility of the dams, here, we investigated the effects of daily exposure to psycho-social stressors (maternal defeat by an aggressive lactating resident and restraint) between pregnancy days 4 and 18 in female rats selectively and bidirectionally bred for high (HAB) or low (LAB) anxiety-related behaviour.

ACTH and corticosterone secretory responses to a mild stressor were found to be low in unstressed lactating HAB and LAB dams (day 8 of lactation) indicating an intact physiological attenuation of the HPA axis at this time. ………..Pregnancy stress significantly increased the reactivity of the hypothalamo-pituitary-adrenal (HPA) axis in lactating HAB, but not LAB rats,

……..reflecting impaired attenuation of the HPA axis selectively in pregnancy-stressed HAB dams.

The high and low anxiety phenotypes were consistent in lactation and not significantly altered by pregnancy stress, despite an elevated level of arousal in pregnancy-stressed HAB dams. In general, HAB dams showed signs of a more protective maternal behaviour compared to LAB dams: (i) in the home cage, HAB dams spent more time in direct pup contact (day 1 of lactation), (ii) during two forms of the pup retrieval test, differing in the level of challenging the dam, HAB dams retrieved the pups faster, and (iii) during the maternal defense test, they were more aggressive towards a virgin intruder compared to LAB and NAB dams.

Pregnancy stress did not alter any of these behavioural measures, except an increase in the speed of pup collection in a novel environment in HAB dams and increased maternal aggression in LAB dams. The results indicate a robust behavioural phenotype of HAB and LAB dams with respect to anxiety and maternal behaviour which was found to be almost unchanged by exposure to pregnancy stress.

………..However, the finding of differential effects of pregnancy stress on the attenuation of the reactivity of the HPA axis in lactation makes HAB and LAB rats a potential animal model for studying genetically determined differences in stress vulnerability and stress-induced maladaptation of the HPA axis post-partum.

++++

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Maestripieri 2005

Abstract – Chicago

A growing body of research on humans suggests that exposure to a stressful family environment or father absence from home during childhood is associated with early female puberty and greater interest in infants among adolescent girls

. ………………..This effect may be mediated by early exposure to harsh and inconsistent maternal care, but the mechanisms by which maternal care affects female reproductive maturation are not known.

The present study reports sex differences in interest in infants among juvenile rhesus macaques similar to those observed in human adolescents.

………… Furthermore, juvenile females that were exposed to harsh and inconsistent maternal care in infancy showed higher interest in infants than controls.

Evidence from cross-fostered females indicated that these effects resulted from early experience and not genetic inheritance from the mother.

…………..There were no significant differences in female age at first conception in relation to the quality of maternal care received during infancy. It could still be an epigenetic factor, or a factor like the child abuse/depression mediation with social support

……….Macaque females exposed to harsh and inconsistent maternal care in infancy tended to have higher cortisol responses to stress and to corticotropin-releasing hormone than controls in the first three years of life.

Furthermore, females with higher cortisol responses to stress exhibited higher interest in infants.

………… These findings suggest that some of the effects of early parental care on female reproductive maturation

may be mediated by developmental changes in the activity of the hypothalamic-pituitary-adrenal axis.

Are these effects directly related to mis-activated attachment systems and their non-optimal functioning, that triggers a response of “I can – and better – do it better, and sooner?”  A daughter’s body  understands that if a mother is this stressed there is something wrong with the environment, which creates an immediacy to reproduce to ensure species’ survival.

This could be an example of a “sickness behavior” that is a response to “sickness” in the environment but is adaptive and life enhancing in that it creates a response designed to heal the sickness in the next generation.

It makes me wonder, for those who become involved with people who have a hard time flourishing, if we are not utilizing some of this same kind of response pattern – in both men and women – that we can “parent” the person better!  This would be a sort of “compensation” pattern, looking to the future, acting on understanding that things were less than optimal in the past but they can be better in the future!

We can see from these studies how the attachment, sexual reproductive, caretaking systems are connected through the operation of oxytocin and vasopressin – influence on and interaction with, all the operational systems of our bodies.  I think life, nature, is always trying to fix what is wrong and make it better.  I don’t think we need to blame and shame ourselves when we participate in this design.  I think that what hope ultimately is about is a HOPE that there will even be a tomorrow!  Lack of hope is the root of the nightmare.

I suppose the information I am recording here from this research is really at the base of “attachment disorders” well before anybody tried to put a name to them.  They really are about brain changes and stress reactions.

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Charmandari et al 2003

Abstract – MD

Stress activates the central and peripheral components of the stress system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis and the arousal/sympathetic system.

The principal effectors of the stress system are

…corticotropin-releasing hormone (CRH),

….arginine vasopressin,

…the proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin,

….the glucocorticoids,

….and the catecholamines norepinephrine and epinephrine.

Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for

….a sense of well-being,

….adequate performance of tasks

….and positive social interactions.

By contrast, inappropriate responsiveness of the stress system may impair growth and development, and may account for a number of endocrine, metabolic, autoimmune and psychiatric disorders.

….The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors and the timing of the stressful event(s), given that prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors.

The developing brain undergoes rapid growth and is characterized by high turnover of neuronal connections during the prenatal and early postnatal life. ….These processes and, hence, brain plasticity, slow down during childhood and puberty, and plateau in young adulthood.

…..Hormonal actions in early life, and to a much lesser extent later, can be organizational, i.e., can have effects that last for long periods of time, often for the entire life of the individual.

……Hormones of the stress system and sex steroids have such effects, which influence the behavior and certain physiologic functions of individuals for life.

……Exposure of the developing brain to severe and/or prolonged stress may result in hyperactivity/hyperreactivity of the stress system,

…….with resultant amygdala hyperfunction (fear reaction),

………decreased activity of the hippocampus (defective glucocorticoid-negative feedback, cognition),

………..and the mesocorticolimbic dopaminergic system (dysthymia, novelty-seeking, addictive behaviors),

………hyperactivation of the HPA axis (hypercortisolism),

………suppression of reproductive, growth, thyroid and immune functions,

……..and changes in pain perception.

These changes may be accompanied by abnormal childhood, adolescent and adult behaviors, including excessive fear (‘inhibited child syndrome’) and addictive behaviors, dysthymia and/or depression,

………..and gradual development of components of the metabolic syndrome X, including visceral obesity and essential hypertension.

Prenatal stress exerted during the period of sexual differentiation may be accompanied by impairment of this process with behavioral and/or somatic sequelae.

…….The vulnerability of individuals to develop varying degrees and/or components of the above life-long syndrome is defined by as yet unidentified genetic factors, which account for up to 60% of the variance.

CRH has marked kindling

and glucocorticoids have strong consolidating properties,

hence both of these hormones are crucial in development and can alone produce the above syndrome.   Not sure what they mean by syndrome

CRH and glucocorticoids may act in synergy, as in acoustic startle, while glucocorticoids may suppress or stimulate CRH, as in the hypothalamus and amygdala, respectively.

………A CRH type 1 receptor antagonist, antalarmin, inhibits both the development and expression of conditioned fear in rats, and has anxiolytic properties in monkeys.

Profound stressors, such as those from sexual abuse, may elicit the syndrome in older children, adolescents and adults.

………Most frequently, chronic dysthymia and/or depression may develop in association with gastrointestinal complaints and/or the premenstrual tension syndrome.

……..A lesser proportion of individuals may develop the classic posttraumatic stress disorder [PTSD],

……..which is characterized by hypocortisolism and intrusive and avoidance symptoms;

………… in younger individuals it may present as dissociative personality disorder.

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Ploj, Roman & Nylander 2003

Abstract – Department of Pharmaceutical Biosciences, Box 591, Uppsala University, SE-751 24 Uppsala, Sweden.

Environmental manipulations early in life may induce persistent alterations in adult behavior and physiology.

The underlying neural mechanisms of these responses are not yet clear. We have previously reported long-term changes in brain opioid peptide levels in male and female Sprague-Dawley rats after short periods (15 min, known as neonatal handling) of maternal separation (MS) until weaning.

To study this further, we investigated behavioural and neurochemical effects of repeated MS in male Wistar rats. The rat pups were separated from their dams in litters for either 360 min (MS360) or 15 min (MS15) daily from postnatal day 1 to 21 or exposed to normal animal facility rearing. Behavioural analysis showed that MS360 rats had increased ultrasonic calls on postnatal day 5 compared to MS15 rats, but not on postnatal day 6. Moreover, the MS360 rats had more animals with higher frequency of calls at day 5 than 6 than the MS15 rats.

Analysis of the opioid peptides

dynorphin B and Met-enkephalin-Arg(6)Phe(7)

with radioimmunoassay 7 weeks after the MS procedure,

revealed long-term neurochemical changes

in several brain areas

and in the pituitary gland.

Immunoreactive

dynorphin B and Met-enkephalin-Arg(6)Phe(7) levels

were affected in the hypothalamus and

dynorphin B levels in the

neurointermediate pituitary lobe,

amygdala,

substantia nigra and the

periaqueductal gray.

Together, these findings show that repeated periods of MS early in life in male Wistar rats affect the development of the ultrasonic call response and

induce long-lasting and possibly permanent alterations in the opioid peptide systems.

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Gustafsson et al 2008

Abstract – Department of Pharmaceutical Biosciences, Division of Pharmacology, Uppsala University, P.O. Box 591, SE-751 24 Uppsala, Sweden.

Early environmental influences can change the neuronal development and thereby affect behavior in adult life. There’s no “can” about this – it DOES!

The aim in the present study was to thoroughly examine the impact of early environmental factors on endogenous opioids by using a rodent maternal separation (MS) model.

The endogenous opioid peptide system

is not fully developed at birth,

and

short- and/or long-term alterations may occur

in these neural networks in animals

exposed to manipulation of the postnatal environment.

Rat pups were subjected to one of five rearing conditions; 15 min (MS15) litter (l) or individual (i), 360 min (MS360) l or i daily MS, or housed under normal animal facility rearing (AFR) conditions during postnatal days 1-21. Measurements of immunoreactive (ir) Met-enkephalin-Arg6Phe7 (MEAP) and dynorphin B (DYNB) peptide levels in the pituitary gland and in a number of brain areas, were performed at three and 10 weeks of age, respectively. MS-induced changes were more pronounced in ir MEAP levels, especially in individually separated rats at three weeks of age and in litter-separated rats at 10 weeks of age.

The enkephalin and dynorphin systems have

different developmental patterns,

dynorphin appearing earlier, which may point at a

more sensitive enkephalin system during the early postnatal weeks.

The results provide evidence that opioid peptides are sensitive for early environmental factors and show that the separation conditions are critical and also result in changes manifesting at different time points.

MS-induced effects were observed in areas related to stress, drug reward and dependence mechanisms.

By describing effects on opioid peptides, the study addresses the

possible role of a deranged endogenous opioid system in the previously described behavioral consequences of MS.

Well, that’s a hell of a beginning!  How is anything supposed to operate correctly when things in the system designed to orchestrate one’s life are this messed up at the start?

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Charmandari , Tsigos & Chrousos 2005

Abstract – MD

The stress response is subserved by the stress system,

……which is located both in the central nervous system and the periphery.

The principal effectors of the stress system include

…corticotropin-releasing hormone (CRH);

…arginine vasopressin;

…the proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin,

…the glucocorticoids;

….and the catecholamines norepinephrine and epinephrine.

Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors.

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Barr et al 2004

Abstract – MD

BACKGROUND: Studies in rodents demonstrate sex differences in neuroendocrine stress axis activity after treatment with alcohol.

In abstinent alcoholics, atypical depressives, and individuals with posttraumatic stress disorder, limbic-hypothalamic-pituitary-adrenal (LHPA)-axis activity is often blunted;

among females in these patient populations, however,

……..resistance to glucocorticoid feedback and increased pituitary reactivity is observed.

Early parental loss is a major life stressor and is a risk factor for both affective disturbances and LHPA-axis abnormalities later in life.

Those of us with abusive parents in our childhood really were born orphans, so we lost a parent even if they were there in body

We wanted to determine whether sex and early life parental absence would interact to influence alcohol-induced alterations in LHPA-axis activity after exposure to ethanol in macaques. METHODS:

…….Animals were reared with their mothers in social groups (MR, n = 94) or without adults in peer-only groups (PR, n = 79).

……..At 5 years of age, they received an intravenous infusion of alcohol (2-2.2 g/kg), and the effects of alcohol, sex, and rearing condition on ACTH and cortisol levels were analyzed by ANOVA.

RESULTS: Peer-reared females had higher ACTH levels than did PR males, MR females, and MR males after alcohol infusion.

……Alcohol-induced cortisol levels were not affected by sex and rearing condition.

CONCLUSIONS: These findings suggest that there are sex differences in glucocorticoid negative feedback, pituitary responsivity, or release of ACTH secretagogues among individuals exposed to early life stress

………..and emphasize the importance of considering sex effects when studying

LHPA-axis dysregulation

………..in alcoholism and other stress-related neuropsychiatric disorders.

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Bosch, Kromer & Neumann 2006

Abstract – Germany

We studied the mechanisms of genetic-early environmental interactions to modulate adult stress-coping and tested the hypothesis that prenatal stress (PS) can differentially alter the consequences of a genetic predisposition to either hyper- or hypo-anxiety.

Exposure of male Wistar rats, bred for high (HAB) or low (LAB) anxiety-related behaviour, to prenatal stress (PS) between pregnancy days 4 and 18 resulted in opposite effects on anxiety in adulthood, i.e.

……… HAB rats became less anxious

………LAB rats became more anxious

compared with their unstressed controls (plus-maze and holeboard).

The high anxiety of HAB controls was accompanied by elevated expression of vasopressin and corticotropin-releasing hormone (CRH) mRNA within the hypothalamic paraventricular nucleus compared with LAB rats.

……….PS reduced CRH mRNA expression in HAB rats but increased vasopressin mRNA expression in LAB rats,

………..which may explain the opposite effects of PS on adult emotionality.

Differential effects of PS were also found with respect to hypothalamo-pituitary-adrenal axis reactivity;

……….the hypothalamo-pituitary-adrenal hyper-response in virgin female HAB controls became attenuated after PS, without affecting plasma corticosterone concentrations in LAB rats.

………. In conclusion, exposure of rats with genetically determined high or low emotionality to PS

………..mitigates the extremes in behavioural and neuroendocrine stress-coping,

…………thus allowing adequate and similar behavioural responses to potentially dangerous stimuli in adulthood.

So this is a coping adaptation that happens in utero, geared toward life in a high stress environment – that those with low anxiety become more anxious and those with high anxiety become less anxious – I guess they are equating emotionality with anxiety?  A sort of leveling the playing field for bad times ahead?

And they know which gene this is that’s moderated?  It must be epigenetically modified?

Differential effects of PS on the activity of the brain vasopressin and CRH systems might represent possible underlying molecular mechanisms.

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Bosch et al 2007

Abstract – Germany

Early life stress is believed to constitute a risk factor for the development of mood disorders later in life.

……..In the present study, we hypothesized that prenatal stress (PS) exerts long-lasting effects in female rat offspring

…………, resulting in impaired adaptations to stress during lactation and, as such, may be a contributory factor to postpartum mood disorders.

PS increased anxiety in adult virgin females compared with controls. During lactation, PS dams nursed significantly less and spent less time with pups compared with controls, whereas dams did not differ in pup retrieval or maternal aggression.

HPA axis reactivity was elevated in response to a mild stressor in PS dams compared to their controls, but not in virgins, with the delta corticosterone response returning to the higher level seen in virgins.

………Moreover, corticotropin-releasing hormone (CRH) mRNA expression within the parvocellular region of the paraventricular nucleus (PVN) was increased in both virgins and dams exposed to PS compared with the relative controls,

……….while the attenuation in expression in lactating controls was abolished following PS.

In addition, arginine vasopressin (AVP) mRNA was increased in the parvocellular, but not magnocellular part of the PVN, in both PS-exposed virgins and lactating dams

…….compared with their relative controls; although expression was also higher in controls during lactation compared with virgins. .

Thus, the present study demonstrates that exposure to PS results in long-lasting behavioural and neuroendocrine alterations in the female offspring, which are manifested during the lactation period.

………..Furthermore, it implicates PS as a potential risk factor for the development of postpartum mood disorders, and that alterations in the HPA axis reactivity, at least partially, are involved.

So the stress of the mother is passed to the daughter, and to their offspring – preparing all to live in a stress filled world.  Talk about being predisposed.

I still think this applies to the experience of my brother, David, as mother carried him through the worst of the homesteading months.  It also applies to me in the reverse way in that while she carried me, life was matching her picture-perfect version of being the happily married, fertile mother.

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OXYTOCIN and  VASOPRESSIN

Neumann, Torner & Wigger 2000

Abstract – Germany

The involvement of brain oxytocin in the attenuated responsiveness of the hypothalamo-pituitary-adrenal axis and the oxytocin systems to external stressors found in pregnant and lactating rats has been studied, including both neuroendocrine and behavioural aspects.

Intracerebroventricular infusion of an oxytocin receptor antagonist (0.75 microg/5 microl), but not of vehicle, elevated basal corticotropin and corticosterone secretion into blood of virgin female, but not of late pregnant or lactating rats.

Oxytocin antagonist treatment further elevated the stress-induced (exposure to the elevated plus-maze or forced swimming) secretion of both corticotropin and corticosterone, but only in virgin and not in pregnant or lactating rats. Thus, corticotropin and corticosterone plasma concentrations remained attenuated in antagonist-treated pregnant and lactating animals. In contrast, infusion of the oxytocin antagonist significantly elevated the stress-induced secretion of oxytocin into blood in pregnant and lactating, but not in virgin, animals, indicating an autoinhibitory influence of intracerebral oxytocin on neurohypophysial oxytocin secretion induced by non-reproduction-related stimuli.

Treatment with oxytocin antagonist 10 min prior to behavioural testing on the elevated plus-maze significantly reduced the anxiety-related behaviour in both pregnant and lactating rats, without exerting similar effects in virgin female rats.

The results demonstrate a tonic inhibitory effect of endogenous oxytocin on corticotropin and, consequently, corticosterone secretion in virgin female rats, an effect which is absent in the peripartum period.

In contrast, an anxiolytic [any substance taken to reduce anxiety] action of endogenous oxytocin was detectable exclusively in pregnant and lactating rats. Therefore, we conclude that the actions of intracerebral oxytocin include independent effects on the responses of the hypothalamo-pituitary-adrenal axis and oxytocin systems to stressors and the anxiety-related behaviour which are modulated by the reproductive state of the animals.

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Neumann et al 2000

Abstract – Germany –MALE RATS

In response to various stressors, oxytocin is released not only into blood, but also within hypothalamic and extrahypothalamic limbic brain regions.

Here, we describe the involvement of intracerebrally released oxytocin in the regulation of the activity of the hypothalamo-pituitary-adrenal (HPA) axis

by infusion of an oxytocin receptor antagonist … either into the lateral cerebral ventricle or into the hypothalamic paraventricular nuclei (PVN), the medio-lateral septum or the amygdala.

Male Wistar rats fitted with a chronic jugular vein catheter and an icv guide cannula or a microdialysis probe targeting the respective brain region 4 days prior to the experiment were blood sampled under basal as well as stressful conditions.

Rats were exposed to the elevated platform (emotional stressor) and/or to forced swimming (combined physical and emotional stressor).

Blockade of the receptor-mediated action of endogenous oxytocin within the PVN resulted in an enhanced basal secretion of ACTH whereas, in response to forced swimming, ACTH secretion was rather reduced, indicating a tonic inhibitory effect of OXT on basal HPA axis activity, but a potentiating action under conditions of stress.

Within the medio-lateral septum, antagonist treatment did not alter basal ACTH secretion, but significantly disinhibited ACTH secretion in response to the elevated platform, but not to forced swimming.

Within the amygdala, no significant effects either on basal or stress-induced HPA axis activity could be found.

The results indicate a differential involvement of brain oxytocin in the regulation of the HPA axis activity which depends both on the site of intracerebral oxytocin release and the stressor the animals are exposed to.

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Neumann et al 2000

Abstract – Germany —–MALE RATS

Oxytocin is a classic reproductive neuropeptide in the female mammal, but its functions in the brain of the male have been less well studied.

As stress induces intracerebral oxytocin release independently of gender,

we postulated that central oxytocin may play a role in the control of stress responses.

In both male and virgin female rats, oxytocin receptor blockade in the brain by intracerebral infusion of a selective oxytocin antagonist …increased the activity of the hypothalamo-pituitary-adrenal (HPA) axis as indicated by a

significantly enhanced basal and stress-induced (exposure to the elevated plus-maze, forced swimming) secretion of corticotropin (ACTH) and corticosterone into blood.

The anxiety-related behaviour on the plus-maze was not altered by the antagonist in either males or females.

Infusion of the oxytocin antagonist into the hypothalamic paraventricular nucleus … resulted in a significant increase in basal release of ACTH in both male and virgin female rats.

These results demonstrate a novel, gender-independent physiological function of endogenous brain oxytocin in the regulation of neuroendocrine stress responses.

Under basal conditions, the inhibition of the HPA axis occurs, at least in part, within the paraventricular nucleus.

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Neumann 2008

abstract – Germany

In addition to various reproductive stimuli, the neuropeptide oxytocin (OXT) is released

,,,both from the neurohypophysial terminal into the blood stream

,,,,and within distinct brain regions in response to stressful or social stimuli.

Brain OXT receptor-mediated actions were shown to be significantly involved in the regulation of a variety of behaviours.

Here, complementary methodological approaches are discussed which were utilised to reveal, for example, anxiolytic and anti-stress effects of OXT, both in females and in males, effects that were localised within the central amygdala and the hypothalamic paraventricular nucleus.

Also, in male rats,

activation of the brain OXT system is essential for the regulation of sexual behaviour, and increased OXT system activity during mating is directly linked to an attenuated anxiety-related behaviour.

Moreover, in late pregnancy and during lactation, central OXT is involved in the establishment and fine-tuned maintenance of maternal care and maternal aggression.

In monogamous prairie voles, brain OXT is important for mating-induced pair bonding, especially in females.

Another example of behavioural actions of

intracerebral OXT is the promotion of social memory processes and recognition of con-specifics,

as revealed in rats, mice, sheep and voles.

Experimental evidence suggests that, in humans, brain OXT exerts similar behavioural effects.

Thus, the brain OXT system seems to be a potential target for the development of therapeutics to treat anxiety- and depression-related diseases or abnormal social behaviours including autism.

Can’t get much clearer than this on the biological and physiological role of attachment related functions — !

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Veenema & Neumann 2008

abstract – Germany

The neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) are acknowledged as important modulators of diverse social behaviours.

Here we discuss recent studies using intracerebral microdialysis to investigate the dynamics of AVP and OXT release patterns within distinct brain regions during the display of social behaviours in rats. Manipulation of local receptor-mediated actions of AVP and OXT via retrodialysis of either agonists or antagonists revealed the behavioural significance of changes in local neuropeptide release.

Alterations in local AVP and OXT within, e.g. the medio-lateral septum, the central amygdala or the hypothalamic paraventricular nucleus (PVN) were associated with intermale and maternal aggression, respectively.

Moreover, increased OXT release within the PVN was associated with male sexual behaviour and successful mating.

Using retrodialysis, we found that AVP released within the lateral septum during the resident-intruder test was associated with anxiety-related behaviour and with non-aggressive social behaviour rather than intermale aggressive behaviour.

In contrast, OXT release within the PVN and the central amygdala correlated positively with the level of maternal aggression.

Interestingly, OXT released within the PVN during sexual activity in male rats was found to be associated with a robust decrease in anxiety-related behaviour up to 4h after mating.

These data illustrate distinct modes of behavioural actions of AVP and OXT, reaching from acute regulation of the respective social behaviour to the long-term modulation of related behaviours including anxiety and social cognition.

In conclusion, measuring the in vivo release patterns of AVP and OXT within distinct brain regions during the display of diverse social behaviours and manipulation of local AVP and OXT activity has yielded new insights into the specific roles of these neuropeptides in the regulation of complex social behaviours.

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Bosch et al 2004

Abstract – Germany

In lactating rats, the neuroendocrine responses of the oxytocinergic system and the hypothalamo-pituitary-adrenal axis to various kinds of stressors are attenuated.

In this study, using intracerebral microdialysis in combination with a highly sensitive radioimmunoassay, we characterized oxytocin (OXT) release within the paraventricular nucleus (PVN), the central amygdala (CeA), and the medio-lateral septum (mS) before, during and after a psycho-social stressor (the maternal defense test) in both the virgin intruder and the lactating resident rat (day 3 of lactation). Within the PVN, local OXT release was found to increase significantly in virgin intruders during exposure to the resident (2.1-fold), as well as in lactating residents when exposed to the virgin intruder, though to a lesser extent when compared with basal levels (1.7-fold).

In contrast, OXT release remained unchanged within the CeA and the mS of both virgin intruders and lactating residents. Release of OXT under basal conditions was clearly above the detection limit of the radioimmunoassay, and did not differ between lactating and virgin rats in any of the brain regions studied.

The results indicate that exposure to the maternal defense test is a relevant stressor for the brain OXT system which becomes activated in both intruder and resident rats, although to varying degrees depending upon their reproductive status and in a region-dependent manner.

The behavioural and/or neuroendocrine functions of intra-PVN released OXT during this psycho-social challenge remain to be clarified.

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Bosch et al 2005

Abstract – Germany

The oxytocinergic system is critically involved in the regulation of maternal behavior, which includes maternal aggression.

Because aggression has been linked to anxiety,

we investigated the maternal aggression and the role of brain oxytocin in lactating Wistar rats selectively bred for high anxiety-related behavior (HAB) or low anxiety-related behavior (LAB) during the 10 min maternal defense test.

HAB dams displayed more maternal aggression against a virgin intruder compared with LAB dams, resulting in more defensive behavior and higher anxiety of HAB-defeated virgins.

The different levels of aggression were accompanied by opposite oxytocin release patterns within the paraventricular nucleus (PVN; HAB, increase; LAB, decrease).

Furthermore, oxytocin release was higher within the central nucleus of the amygdala (CeA) of HAB dams compared with LABs.

A direct correlation between the offensive behavior displayed during the maternal defense test and local oxytocin release was found in both the PVN and CeA. Using retrodialysis, blockade of endogenous oxytocin action by infusion of an oxytocin receptor antagonist … into the PVN or CeA reduced maternal aggression of HAB dams, whereas infusion of synthetic oxytocin into the PVN tended to increase aggression toward the intruder in LAB dams.

There were no significant differences in oxytocin receptor mRNA expression or oxytocin receptor binding between lactating HAB and LAB dams.

Therefore, differences in intracerebral release patterns of oxytocin, rather than differences at the level of oxytocin receptors, are critical for the regulation of maternal aggressive behavior.

So what, biologically and physiologically goes so wrong in cases like my mother where she was my attacker?

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Gobrogge et al 2007

Abstract – FL

Male prairie voles (Microtus ochrogaster) display mating-induced pair bonding indicated by social affiliation with their female partners and aggression toward unfamiliar conspecifics.

In the present study, we characterized their aggression associated with pair bonding and examined the related neuronal activation and neurochemical architecture.

Males that were pair-bonded for 2 weeks displayed intense levels of aggression toward a female or male conspecific stranger but maintained a high level of social affiliation with their familiar female partners. These social interactions induced increases in neural activation, indicated by increased density of Fos-immunoreactive staining (Fos-ir) in several brain regions including the

……..bed nucleus of the stria terminalis (BNST),

……..medial preoptic area (MPOA),

……….paraventricular nucleus (PVN),

……….anterior cortical (AcA),

………and medial nuclei (MeA) of the amygdala.

In the anterior hypothalamus (AH), increased density of Fos-ir staining was found specifically to be associated with aggression toward unfamiliar female or male strangers.

In addition, higher densities of AH cells that were stained for tyrosine hydroxylase (TH) or vasopressin (AVP) were also labeled with Fos-ir in these males displaying aggression toward a conspecific stranger compared with males displaying social affiliation toward their female partner. Together, our results indicate that dopamine and vasopressin in the AH may be involved in the regulation of enduring aggression associated with pair bonding in male prairie voles

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Bosch et al 2007

Abstract – Germany

Brain oxytocin (OT) regulates aspects of emotionality and stress coping including maternal behavior and maternal aggression.

Maternal aggression

correlates with the amount of OT released within

the paraventricular nucleus (PVN) and the central amygdala (CeA).

OT, a key neurotransmitter or neuromodulator, is likely to modulate other neurotransmitter systems.

Here, we investigated the dynamic changes in extracellular concentrations of the amino acids aspartate, glutamate, gamma-aminobutyric acid (GABA), serine, histidine, arginine and taurine in the PVN and CeA in lactating rats bred for high (HAB) and low (LAB) anxiety-related behavior under basal conditions and during maternal aggression. Further, to determine whether local OT is involved in the regulation of amino acid release we infused a selective OT receptor antagonist (OTA) via local retrodialysis.

Within the CeA, HAB and LAB dams differed in the basal release of glutamate and arginine. Infusion of a selective OTA increased the concentrations of glutamate and aspartate in LAB dams and GABA in HAB dams. In OTA-treated HAB and LAB dams taurine levels increased during maternal aggression.

Within the PVN, the highly-aggressive HAB dams showed a more pronounced increase in aspartate and serine levels; the latter being attenuated by local OTA administration. However, OTA did not affect the level of any amino acid in the LAB dams.

Thus, the extracellular concentrations of selected amino acids differed between lactating HAB and LAB dams under both basal conditions and following maternal aggression. The effects of OT within the CeA and PVN on maternal aggressive behavior might be related to its regulation of local amino acid release.

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Ebner et al 2005

Abstract – Austria

… the release of oxytocin (OXT) occurs in various hypothalamic and extrahypothalamic brain areas.

In the present study, we investigated in male rats whether swim stress triggers the release of OXT in the central amygdala (CeA), a key area in processing emotions and stress responses.

Further, we examined the physiological significance of OXT released within the CeA for behavioral responses during forced swimming as well as

effects on the local release of selected amino acids including glutamate, aspartate, arginine, taurine, and GABA, which are thought to modulate processing of emotions.

Exposure to a 10-min forced swimming session caused a significant increase in OXT release (200%, p<0.01) within, but not outside, the CeA

Administration of the OXT receptor antagonist …into the amygdala before and during exposure to swimming reduced the floating time by 55% (p<0.05) and increased the swimming time by 29% (p<0.05) indicative of a more active stress-coping strategy.

Simultaneously, local administration of the OXT receptor antagonist caused a significant increase in the stress-induced release of the excitatory amino acids glutamate and aspartate, whereas the basal release of these amino acids remained unchanged.

Taken together, these findings demonstrate a significant activation of the oxytocinergic system in the CeA in response to swim stress.

Furthermore, our data indicate that OXT

…… receptor-mediated mechanisms within the amygdala

……are involved in the generation of passive stress-coping strategies, which might be mediated at least in part via its inhibitory influence on the local release of excitatory amino acids during stress.

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Oliet et al 2007

Abstract – Institut National de la Santé et de la Recherche Médicale, Unité 862, Université Victor Segalen Bordeaux 2, Bordeaux 33077, France.

The probability of neurotransmitter release at the nerve terminal is an important determinant of synaptic efficacy. At some central synapses, the postsynaptic, or target, neuron determines neurotransmitter release probability (P(r)) at the presynaptic terminal. The mechanisms responsible for this target-cell dependent control of P(r) have not been elucidated. Using whole-cell patch-clamp recordings from magnocellular neurosecretory cells in the paraventricular and supraoptic nuclei of the hypothalamus, we demonstrate that inhibitory, GABA synapses specifically onto oxytocin (OT)-producing neurosecretory cells exhibit a low P(r) that is relatively uniform at multiple synapses onto the same cell. This low P(r) results from a two-step process that requires the tonic release of OT from the postsynaptic cell.

The ambient extracellular levels of neuropeptide are sufficient to activate postsynaptic oxytocin (OT) receptors and trigger the

Ca2+-dependent production of endocannabinoids,

which act in a retrograde manner at presynaptic cannabinoid CB1 receptors to decrease GABA release.

The functional consequence of this tonic inhibition of GABA release is that all inhibitory inputs facilitate uniformly when activated at high rates of activity. This causes inhibition in the postsynaptic cell that is sufficiently powerful to disrupt firing. Blockade of CB1 receptors increases P(r) at these synapses, resulting in a rapid depression of IPSCs at high rates of activity, thereby eliminating the ability of afferent inputs to inhibit postsynaptic firing.

By playing a deterministic role in GABA release

at the afferent nerve terminal, the postsynaptic OT neuron effectively filters synaptic signals and

thereby modulates its own activity patterns.

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Kovacs et al 1990

Abstract – Hungary

Cocaine is a widely used drug of abuse. One of the characteristic effects of this stimulant drug in the CNS of mice is the induction of motor hyperactivity. It was demonstrated that cocaine-induced motor hyperactivity could be blocked by pimozide, a dopamine receptor blocker, suggesting that dopamine was involved in cocaine-induced hyperactivity.

Oxytocin, a neurohypophyseal neuropeptide, also partially antagonized cocaine-induced motor hyperactivity.

Moreover, oxytocin antagonized the increased utilization of dopamine, elicited by cocaine in the nucleus accumbens.

The data suggest that oxytocin may influence the behavioural effects of cocaine by affecting dopaminergic neurotransmission in some regions of the brain.

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Dong et al 2004

Abstract – Stanford

Synaptic plasticity in the mesolimbic dopamine (DA) system is thought to contribute to the neural adaptations that mediate behavioral sensitization,

a model for core aspects of addiction.   Learning?

Recently, it has been demonstrated that

multiple classes of drugs of abuse,

as well as acute stress,

enhance strength at excitatory synapses on midbrain DA neurons.

Here, we show that both the cocaine- and stress-induced synaptic enhancement involves an up-regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.

This enhancement requires the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluRA as evidenced by its absence in mice lacking this subunit.

The cocaine-elicited, but not the stress-elicited, synaptic potentiation in DA neurons was blocked by a D1-like receptor antagonist, indicating that the in vivo triggering mechanisms differ for these forms of experience-dependent synaptic modification.

Surprisingly, behavioral sensitization to cocaine was elicited in GluRA(-/-) mice, indicating that potentiation of excitatory synaptic transmission in DA neurons is not necessary for this form of behavioral plasticity.

However, GluRA(-/-) mice did not exhibit a conditioned locomotor response when placed in a context previously paired with cocaine, nor did they exhibit conditioned place preference in response to cocaine.

We suggest that the drug-induced enhancement of excitatory synaptic transmission in midbrain DA neurons, although not required for behavioral sensitization per se, may contribute to the attribution of incentive value to drug-associated cues.

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Sarnyai & Kovacs 1994

Abstract – Harvard

Oxytocin (OXT), a neurohypophyseal hormone, has a wide range of behavioral effects outside its classic peripheral endocrine functions.

OXT involvement in adaptive central nervous system processes has been demonstrated as an inhibitory, amnestic action on learning and memory in different paradigms.

Because adaptation and learning are likely to be involved in the neural events leading to drug tolerance and dependence, the question logically arose whether OXT is able to influence the development of tolerance of and dependence on abused drugs.

In this review, we summarize our results on the effects of OXT on opiate

(including morphine, heroin, and the endogenous opiates beta-endorphin and enkephalin) tolerance and dependence, heroin self-administration, psychostimulant-induced behavioral changes, and behavioral tolerance and sensitization. The sites and mechanisms of action and the possible physiological role of OXT are also discussed. …

OXT inhibited the development of tolerance to morphine, heroin, beta-endorphin, and enkephalin, OXT also inhibited the development of cross-tolerance between the predominantly mu-agonist heroin and the predominantly delta-agonist enkephalin in mice. Naloxone-precipitated morphine withdrawal syndrome was also attenuated by OXT.

Heroin self-administration was decreased by OXT administration in heroin-tolerant rats. OXT inhibited cocaine-induced exploratory activity, locomotor hyperactivity, and stereotyped behavior in rats and in mice. Behavioral tolerance to cocaine was also attenuated by OXT. On the contrary, OXT stimulated the development of behavioral sensitization to cocaine. OXT did not alter the stereotyped behavior induced by amphetamine. In the second series of experiments, the sites of action of OXT on drug-related behavior were investigated. …administration of an OXT-receptor antagonist inhibited the effects of peripherally administered OXT on morphine tolerance, heroin self-administration, and cocaine-induced sniffing behavior. This suggests the central, intracerebral location of OXT target sites.

Local IC microinjection of OXT in physiological doses into the posterior olfactory nucleus, tuberculum olfactorium, nucleus accumbens, central amygdaloid nucleus, and the hippocampus inhibited the development of tolerance to and dependence on morphine as well as cocaine-induced sniffing behavior and tolerance to cocaine. The physiological role of endogenous OXT in acute morphine tolerance has also been demonstrated, since OXT antiserum (ICV) and OXT-receptor antagonist (injected into the basal forebrain structures) potentiated the development of morphine tolerance.

Finally, we investigated the possible mechanisms of action of OXT on drug related behavior. Both morphine tolerance and dependence, and cocaine administration, increased dopamine utilization in the mesencephalon and in the nucleus accumbens, respectively.

OXT treatment decreased the alpha-methylparatyrosine-induced dopamine utilization in the mesencephalon and in the nucleus accumbens-septal complex. Chronic OXT treatment decreased the number of apparent binding sites of dopamine in the basal forebrain area. It also inhibited a cocaine-induced increase in dopamine utilization in the nucleus accumbens, but not in the striatum.

In light of this information, it appears that OXT inhibits the development of opiate tolerance, dependence, and self-administration as well as the acute behavioral actions of and chronic tolerance to cocaine.

This suggests the possible role of this neuropeptide in the regulation of drug abuse. Therefore, OXT may act as a neuromodulator on dopaminergic neurotransmission in limbic-basal forebrain structures to regulate adaptive CNS processes leading to drug addiction.

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Feltenstein & See 2008

Abstract – Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. feltens@musc.edu

Drug addiction presents as a chronic relapsing disorder characterized by persistent drug-seeking and drug-taking behaviors. Given the significant detrimental effects of this disease both socially and economically, a considerable amount of research has been dedicated to understanding a number of issues in addiction, including behavioural and neuropharmacological factors that contribute to the development, loss of control and persistence of compulsive addictive behaviors. In this review, we will give a broad overview of various theories of addiction, animal models of addiction and relapse, drugs of abuse, and the neurobiology of drug dependence and relapse. Although drugs of abuse possess diverse neuropharmacological profiles,

activation of the mesocorticolimbic system, particularly the ventral tegmental area,

nucleus accumbens,

amygdala and

prefrontal cortex

via dopaminergic and glutamatergic pathways, constitutes a common pathway by which various drugs of abuse mediate their acute reinforcing effects.

However, long-term neuroadaptations in this circuitry likely underlie the transition to drug dependence and cycles of relapse.

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Zheng, Bosch & Ronnekleiv 2005

Abstract – Portland

It has been known for a number of years that mu-opioid receptor agonists (e.g., morphine, beta-endorphin, and enkephalin) inhibit luteinizing hormone (LH), vasopressin (VP), and oxytocin (OT) release and stimulate prolactin secretion ………..in rodents and primates by an action at the level of the brain.

…………Also, electrophysiological studies have established that hypothalamic neurons, including gonadotropin-releasing hormone (GnRH), VP, OT, beta-endorphin, and dopamine neurons, are responsive to mu-receptor activation.

Although mu-receptor expression has been demonstrated in the hypothalamus, there have been few studies localizing these receptors in neurosecretory neurons.

Therefore, we sought to document mu-opioid receptor mRNA expression in immunocytochemically identified hypothalamic neurons. The brains from both female and male guinea pigs were examined by using in situ hybridization and immunocytochemistry. The studies revealed that mu-receptor mRNA was expressed in different diencephalic regions including the preoptic area, the bed nuclei stria terminalis, the paraventricular nucleus thalamus, and the anterior hypothalamus, as well as the supraoptic (SON), paraventricular (PVH), ventromedial, dorsomedial, and arcuate nuclei of the hypothalamus.

Importantly, mu-opioid receptors were expressed in subpopulations of GnRH neurons, dopamine neurons , depending on neuronal location, beta-endorphin neurons , and VP.

………Because mu-opioid receptors couple via G-proteins to activate inwardly rectifying potassium channels and to inhibit calcium channels

, the presence of these receptors is likely to play a major role in directly controlling the excitability of hypothalamic neurons.

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Strange thought/question:  “Does a bird ever stumble and fall?”

Also, am putting some of the pain info in the attachment section on pain – it is so hard to know where to draw the line with all this information – how to categorize it.  The opioid receptors are involved at the basis of attachment —

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Sarnyai 1998

Abstract – Rockefeller U, NY

Oxytocin (OT) has been implicated in neuroadaptive processes such as learning, memory, and social-affiliative behavior as well as in the regulation of physiological responses leading to adaptation to the changing external and internal environment.

How could this neuropeptide NOT be a part of trauma reactivity?

Drugs of abuse constitute a major challenge to the homeostasis of the body and behavior. Drug tolerance, dependence and addiction may involve neuroadaptive mechanisms related to learning and memory at cellular and systems levels.

Neuropeptides OT and vasopressin (VP) might be involved in these processes based on their effects on neuroadaptation and on their neuroanatomical localization and pharmacological actions.

It has been demonstrated that both OT and VP have modulatory effects on opiate and alcohol tolerance and dependence. …We have shown that OT inhibits acute cocaine-induced locomotor hyperactivity, exploratory activity and stereotyped behavior in rodents. Furthermore, OT facilitated, whereas VP inhibited the development of behavioral sensitization to cocaine.

In a different model, OT inhibited the development of tolerance to the stereotyped behavior-inducing effects of cocaine as well as cocaine intravenous self-administration in rats. We demonstrated that OT acts through its specific receptors in the basal forebrain and in the hippocampus.

OT and VP contents in the hypothalamus and limbic structures were altered by acute and chronic cocaine administration in a dose-dependent and region-selective manner. The differential plasticity of the brain OT-ergic and VP-ergic neurotransmissions in response to cocaine may underlie the differences in the involvement of these neuropeptides in cocaine addiction.

Interaction of OT with dopaminergic neurotransmission in the nucleus accumbens, a key brain structure in drug addiction, as well as OT-ergic regulation of hippocampal processes may be among the mechanisms of action through which OT modulates neuroadaptation to cocaine. A better understanding of the role of OT in neuroadaptation to cocaine may provide an insight into both the mechanisms of neuropeptide actions in the brain as well as into the neurobiology of drug addiction.

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Sarnyai 1988

Abstract – Hungry

It has previously been shown that endogenous oxytocin (OXT) inhibits the development of acute morphine tolerance. The role of OXT receptors in the central nervous system (CNS) was therefore studied by using a specific OXT receptor antagonist, …injected into the posterior olfactory nucleus, central amygdaloid nucleus, ventral hippocampus, caudate nucleus or lateral cerebral ventricle.

The antagonist facilitated the development of tolerance to morphine when injected into the

…posterior olfactory nucleus,

….central amygdaloid nucleus or

….ventral hippocampal areas,

which are known to contain OXT binding sites. When administered into the caudate nucleus (with no OXT binding sites) or the lateral cerebral ventricle, it had no effect on morphine tolerance. Our results suggest that the

limbic forebrain OXT receptors

play an important inhibitory role in adaptive responses to morphine.

All this ties into the attachment reality that our entire system begins in utero with an addiction to endogenous opioids!!!  The system is set up so that we never get enough of each other through social bonding – orchestrated from the sense of smell at the center of the limbic brain, and through the limbic brain – and the amygdala which moderates our fear response – or our hippocampus which processes our memories

We are supposed to remember that it feels good to be a member of our species!  Use of outside drugs creates a perversion of the system we were evolved to exploit for our own protection, survival, enjoyment.  All the seeking and reward patterns are in place for us to be together – and enjoy it – unless things went terribly wrong in the beginning, affecting development of the limbic brain, etc.

++++

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Brunton & Russell 2008b

Abstract – Laboratory of Neuroendocrinology, Centre for Integrative Physiology, University of Edinburgh, Scotland, UK.

Oxytocin

synthesized by

magnocellular neurons in the supraoptic and paraventricular nuclei

plays an important role in mammalian parturition.

Accordingly, in late pregnant rats,

oxytocin neurons are restrained from premature activation and stimulated oxytocin secretion is inhibited,

preserving the expanded neurohypophysial oxytocin stores

for parturition.

A wide range of stressors stimulate oxytocin secretion in the rat. Some physical stressors, in particular immune challenge with systemic interleukin-1beta (IL-1beta, a cytokine that mimics infection)

signal to magnocellular oxytocin neurons

via brainstem noradrenergic neurons.

Afferents relaying information from the uterus and birth canal also converge onto brainstem noradrenergic neurons and are robustly activated at parturition.

Thus, quiescence of these inputs may be important in minimizing the risk of preterm labor. Focusing on an immune challenge model (since infection is a major cause of preterm labor in women), we have found that the responsiveness of oxytocin neurons to IL-1beta is markedly suppressed in late pregnancy.

Here we discuss the mechanisms involved,

which include induction of central inhibitory opioid tone

by the progesterone neurosteroid metabolite, allopregnanolone,

and act to prevent activation of oxytocin neurons by inappropriate stimuli at the end of pregnancy.

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Douglas, Johnstone & Leng 2007

Abstract – Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK. Alison.j.douglas@ed.ac.uk

During pregnancy body weight, and particularly adiposity, increase, due to hyperphagia rather than decreased energy metabolism. These physiological adaptations provide the growing fetus(es) with nutrition and prepare the mother for the metabolically-demanding lactation period following birth. Mechanisms underlying the hyperphagia are still poorly understood. Although the peripheral signals that drive appetite and satiety centers of the brain are increased in pregnancy, the brain may become insensitive to their effects.

For example, leptin secretion increases but hypothalamic resistance to leptin actions develops. However, several adaptations in hypothalamic neuroendocrine systems may converge to increase ingestive behavior.

Oxytocin is one of the anorectic hypothalamic neuropeptides.

Oxytocin neurons, both centrally-projecting parvocellular oxytocin neurons

and central dendritic release of oxytocin from magnocellular neurons,

may play a key role in regulating energy intake.

During feeding in non-pregnant rats, magnocellular oxytocin neurons, especially those in the supraoptic nucleus, become strongly activated indicating their imminent role in meal termination.

However, in mid-pregnancy the excitability of these neurons is reduced,

central dendritic oxytocin release is inhibited a

nd patterns of oxytocin receptor binding in the brain alter.

Our recent data suggest that lack of central oxytocin action may partly contribute to maternal hyperphagia.

However, although opioid inhibition is a major factor in oxytocin neuron restraint during pregnancy and opioids enhance food intake, an increase in opioid orexigenic actions were not observed.

While changes in several central input pathways to oxytocin neurons are likely to be involved, the high level of progesterone secretion during pregnancy is probably the ultimate trigger for the adaptations.

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Weiss et al 2001

Abstract – Scripps Research Institute, La Jolla, CA

The development of addiction and vulnerability to relapse following withdrawal

…… is proposed to be the result of neuroadaptive processes within the central nervous system

…………… that oppose the acute reinforcing actions of drugs of abuse.

So if I think about this with cigarettes, they would be saying that my addiction to cigs and vulnerability to relapse if I quit is because of these neuroadaptive processes within the CNS that oppose the reinforcing action of the cigs?  I’m sorry, but this doesn’t make sense to me!  A paradox!  How can the addiction be a result of something that opposes the reinforcement action of the drug?  There has to me something going on in the MIDDLE that I am not getting here!

I am trying to translate these processes as I go along, but am encountering my strange “dyslexic” process in that these facts all seem to be presented backwards!

If we are “addicted” to being with our species as social beings, then any separation/withdrawal from our group into isolation would then NEED to undergo a “relapse” of the separation/isolation so that the positive consequence of the relapse would be to rejoin the group and “quit” being alone.

Our nervous system, and the oxytocin set up would be geared to ensuring that we remain a part of the group – and create distress at separation

And what does it feel like to be the one that is rejected from “the group?”  Expunged, abandoned?  What does it feel like to be the one the mother does not want, the one that is excluded from the family?  And how can this condition NOT get built right into the circuitry of the brain and all the stress reactions that are forming themselves from birth?

It never stops hurting.  One never stops wanting to be with the one that rejects us, that does not want us.  And there is no way we cannot feel shame in connection with the loss of our caregiver – or lover – our attachment figure.  Because this all connects to the physiological shame reaction in the body – the same circuitry being used for rupture and repair, no matter what the circumstances or perceptions.  It creates in us both a terror and a longing that never go away – and depending on how young we were when these rupture without repair rejection circuits were created, the deeper the rut and the greater the despair anywhere down the road of life when we experience similar circumstances again.

And it is the nature of the attachment system that we would seek reattachment once distress is felt that activates this system naturally in the first place.  But we are left with the abiding grief that comes from knowing the one we long for, the connection we seek in our despair, is the very one that rejected and hurt us in the beginning.

We want to scream to them, “Don’t you care about me?  What is wrong with me?”  We cannot easily imagine that the wrong lies somewhere else.  In that other person’s actions, or in the toxicity of an environment.  If we have even the glimmerings of a conscious self, we will take this responsibility for isolation onto ourselves, because it is IN us.  And we must realize that the defensiveness of insecure attachment disorders usually means that these people completely lack the ability to empathize, and will not begin to reverberate within themselves in response to our pain – because they can no longer feel their own.

This is why trauma dramas are so easy to fall into, the reenactments that continue to plague us throughout our lives.  We cannot tell the difference — what belongs to the past and what is happening in the present share the same circuits and pathways in the brain and body.  The experience IS the same experience, not a different one, not a separate one.  Only by finding our way onto a different pathway in the present can we begin to separate this past from this present.

In the attachment system physiologically, it makes no difference if we reject our drug or the drug rejects us.  We are still left with the excruciating reality of what rejection and withdrawal feel like.  We are biologically and genetically programmed to feel as badly as we possibly can when the natural attachment process is interrupted.  And those who have substituted other chemicals as interplay agents within this system are going to be left with the same process.

In my thinking, addiction to a person is NOT the same thing as addiction to an external drug, because the very systems that drug addiction subsumes are DESIGNED to keep us attached to people.  Yet when our attachment people fail us, we cannot ask why they do this – that is theirs, on their side of the fence.  We cannot know why.  Either they cannot love us, or they do not love us.  Plain and simple.  We are the ones left with the pain.  If they could fruitfully share our pain through empathy this process could go differently.  But usually the cannot or will not, and we are left alone in the process of FEELING alone because we are alone.

Our genetics and physiology will feed this despair system until something comes along so that we can deactivate our attachment system (which is a large part of what gangs and drug addiction are attempts to accomplish).  An attachment system is deactivated either by our own sense of inner security which means we are not under duress and distress that requires us to be in contact with others, or it will be deactivated because we come into adequate contact with others – the old “adequate social support” factor.

Part of the difficulties we confront in this process is that all our historic experiences regarding past activities related to attachment – either with humans or through substitute opioid substances, will come into play right when we need new ones the most.  It is like having balls and chains around us, we are shackled to past learnings and past cues.

This is another area that those of us with severe child abuse issues are at a disadvantage.  Our HPA axis is geared differently regarding experiences of stress, and that includes all stress, good or bad.  Searching for novelty creates stress – and requires us to use all the passive and active coping skills we have developed.  Only some of us don’t have the tools we need here, and it makes the going just that much more difficult for us.  So we have to start where we are and work with what we’ve got.

We have to do what we can do, and I mean that literally.  If we can make toast, we make toast.  If we can ride a bicycle, we ride a bicycle.  Plant a garden, trim a tree, take a walk, paint a picture, write an email, find a friend.  All the little accomplishments that we have gained, knowing our right hand from our left, tying our shoe, washing clothes, fixing things.  These things pass time, one moment after another, and they are using coping pathways in our brain.  Using them reinforces them.  No matter how difficult it may be.

Grieving sucks, and some of us have been grieving all of our lives.  It seems that only when we are with the ones we love does the grieving fade into the background.  Often, then, it is the absence of the grief from the pain of being spurned that feels so good to us we mistake it for something more positive than what it is.  Absence of pain and suffering is not the same thing as experiencing joy.  And yet in some of these problematic relationships we have not only experienced the absence of the suffering at times, but we HAVE felt abounding joy.  There, my friend, is where we get into the deepest trouble.  Because we seem to have an innate balancing process going on that allows us to suffer all sorts of inequities in relationships that, to us, are only a balance to the joy.  And we think this is OK – we hate to let go – and we know that we can’t.

I am with you on this.  I am going through it as I write these words, forcing myself away from the phone so I do not call the man I miss so much and long to be with.  This is the pain of withdrawal riding close beside the risk of relapse.  Yet I would feel ashamed to explain to you the details of this relationship that has endured for me for 8 years.  I would be ashamed.  And it is because I now see that this sense of shame is connected to the patterns contained within the complex of the attachment system that I feel finally motivated to end this relationship, as sad as it makes me, as deeply as this pain today shares the circuits of all my pains from the past.  Because how can I share with you what I cannot accomplish myself?  I cannot.

It was the unbearable and overwhelming pain I felt nearly three years ago that motivated me to pursue research to find out what this pain was, why I had it, why I could not escape it.  It lead me instantly to neuroscientific descriptions of brain development from birth in hostile environments under abusive and neglectful conditions that were more than any person could bear.  I learned quickly that I never learned how to soothe myself.  Now I make toast to soothe myself.  I write, I hope for something different and I try to figure out how to get there.  But there are often tears swimming behind my eyes.  I will not lie to you about that.  I am still trying to understand how I could be this in love with a man who until recently lived with two other women – one on weekends and one during the week – he’s down to one now that he lives in his mansion – while he never would cross my threshold.

Yet I dearly loved every moment with him and that is the truth.  I miss him terribly and that is the truth.  He IS special and unique, and I know how I can love him.  BUT he also, as far as I can now tell, has a narcissistic personality disorder – and there’s no healing that – he’s 71 years old.  His defenses are rigid, inflexible, and impenetrable and hones to perfection from a lifetime of use.  I will forever be left standing on the outside, as I was throughout my entire childhood, while the other(s) “more deserving” are gathered around him on the inside.  And today I will not call him.  I will not go over to his shop and visit for one hour, two, three, four.  I will not ride around town with him on tow calls, or travel beside him over the majesty of the desert landscape.  I will not inquire about his health, or discuss with him the state of global affairs.  I will not hear the rich, sweet, mellow, tenor of his voice, or feel the light touch of his hand brush occasionally across my knee as I sit beside him. And I miss him.  I will probably miss him the rest of my life.

Now back to the tangible research to see if I can learn something new that I can put to good use.  Nobody can do this for me but myself.  Seeing him will fix nothing.  The only chance I have for things really getting better, moving further toward the flourishing end, is to NOT see him, as hard as this is.  I called my sister.  She understands.

These changes lead to

….. impairment in the mechanisms that mediate positive reinforcement

……and the emergence of affective changes such as anxiety, dysphoria, and depression during withdrawal.

Considerable evidence exists implicating perturbations in DA [dopamine] and 5-HT transmission in the nucleus accumbens–

……………neurochemical systems that are activated by cocaine and ethanol self-administration

……………. and deficient during withdrawal-

……….as potential substrates for these affective changes.

Affective because they involve the limbic system?

In addition, growing evidence suggests that enhanced CRF release in the central nucleus of the amygdala represents a mechanism underlying the anxiogenic and stress-like consequences of withdrawal that are common to all drugs of abuse.

A growing body of evidence also implicates

…dysregulation of the non-neuroendocrine CRF stress system within the central nucleus of the amygdala

…as a common factor in the anxiogenic and aversive consequences of withdrawal from drugs of abuse.

If this attempt to quit seeking proximity exists within a system that is supposed to make us anxious when we are exposed to all cues that should make us seek social support, it makes sense that the body is NOT going to support our decision to be alone/withdrawn/isolated?

We are compulsively not supposed to be alone, are supposed to compulsively seek the company of our conspecifics.  This would have to do with the activation of our attachment system that creates a process in us where we seek reattachment – from birth – through the lifetime when stressed.

It would also be connected to the reasons why it is so hard to get out of “bad” relationships – when being with that person creates the stress, and yet when we try to leave our attachment system is activated that makes us seek their company.  This is the bind that children are in when exposed to abuse from their caregivers!

The emotional dysregulation in the limbic brain regions that is created during brain developmental stages in interaction with toxic caregivers is not going to be our friend when we are trying to extricate ourselves from difficult and toxic relationships later on.  This is one of the sticky areas for people with insecure attachment histories and styles of attachment of any kind, certainly for the disoriented/disorganized ones.  How do we differentiate the feelings for the person, the feelings generated in the relationship, from the feelings of having an activated attachment system?

I might finally be getting to the point where I can separate from this relationship, but it has taken me eight years to get to this point!  That is because attachment is activating the same systems as drug addictions use in the brain! How timely it is for me to find this research today – well, really, I went looking for it knowing it was somehow connected in relationships – because I am trying to take my stand, make my stand – and this emphasizes the necessity of awareness and consciousness, so that I can avoid having my activated attachment system make my reactions for me – rather than being able to make choices, different choices, about how to attach, to whom, when, where, why…

Moreover, a possible link may exist between long-lasting abnormalities in CRF function in the CeA and vulnerability to relapse during protracted abstinence.

Another presumably critical element contributing to the chronic relapsing nature of drug addiction is the learned responses to drug-related stimuli.

……The long-lasting efficacy of drug- and alcohol-associated contextual stimuli in eliciting drug-seeking behavior in animal models of relapse resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans

………….and confirms a significant role of learning factors in the long-lasting addictive potential of cocaine.

With cocaine, D1-dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala

……….may be important substrates for the motivating effects of drug-related environmental stimuli.

……….With ethanol, available data suggest a role for opioid receptors in the mediation of conditioned drug-seeking behavior.

Finally, conditioning factors (i.e., exposure to drug-associated stimuli) and stress can interact to augment vulnerability to relapse. This finding emphasizes that it will be important to consider the simultaneous effects of multiple environmental triggers for relapse in the development of treatment and medication strategies.

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Buller, Hamlin & Osborne 2005

Abstract – 2005

In opiate addicts or patients receiving morphine treatment, it has been reported that the immune system is often compromised.

The mechanisms responsible for the adverse effects of opioids on responses to infection are not clear but it is possible that central and/or peripheral opioid receptors may be important.

……We have utilized an experimental immune challenge model in rats,… no effect of blocking peripheral opioid receptors was detected in the central nucleus of the amygdala (CeA) or dorsal bed nucleus of the stria terminalis (BNST).

………We next determined the effect of blocking both central and peripheral opioid receptors with naloxone and, when compared to the naloxone methiodide pre-treated group, a further 60% decrease in Fos-IR mPVN CRH neurons induced by IL-1beta was detected, which was attributed to block of central opioid receptors.

………Similar comparisons also detected decreases in Fos-IR neurons induced by IL-1beta in the VLM A1, VLM C1 and NTS A2 catecholamine cell groups, area postrema, and parabrachial nucleus. In contrast, pre-treatment with naloxone increased Fos-IR neurons in CeA (98%) and dorsal BNST (72%).

These results provide novel evidence that endogenous opioids can influence central neural responses to systemic IL-1beta and also suggest that the differential patterns of activation may arise because of actions at central and/or peripheral opioid receptors that might be important in regulating behavioural, hypothalamic-pituitary-adrenal axis and sympathetic nervous system responses during an immune challenge.

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Weiss et al 2001

Abstract – Scripps Research Institute, La Jolla, CA

The conditioning of cocaine’s pharmacological actions with environmental stimuli is thought to be a critical factor in long-lasting relapse risk associated with cocaine addiction.

We want our attachment relationships to last.  Over time, we become “conditioned” to our relationships in any way that they exist – and to the environmental stimuli that go with them.  We are, therefore, at no less of a “long-lasting relapse risk” trying to extricate from relationships that are not causing us to flourish.

The opioid system would build within itself an “enduring vulnerability to relapse” if it meant that our connections with one another would be more likely as a species to be maintained.  Read “drug-seeking behavior” as people seeking behavior.  Extinction of our desire to be together would have meant extinction of ourselves as individuals, extinction of our species as a whole.  Of course there’s a resistance to extinction of seeking opioid fulfillment!  Only I am talking about our natural, endogenous ones – the drug substitutes, using these same systems in the body, are harmful – just as some of our relationships with people in our lives either are or have been.

This is a “I will stick with you” system in the brain – whatever fills those starving opioid receptors.

To study the significance of environmental stimuli in enduring vulnerability to relapse, the resistance to extinction of drug-seeking behavior elicited by a cocaine-related stimulus was examined.

Male Wistar rats were trained to associate discriminative stimuli (S(D)) with the availability of intravenous cocaine (S(+)) vs. the availability of non-rewarding (S(-)) saline solution, and then placed on extinction conditions during which intravenous solutions and S(D) were withheld. The rats were then presented with the S(+) or S(-) alone in 60-min reinstatement sessions conducted at 3-day intervals. To examine the long-term persistence of the motivating effects of the cocaine S(+), a subgroup of rats was re-tested following an additional three months of abstinence during which time the rats remained confined to their home cages. Re-exposure to the cocaine S(+) selectively elicited robust responding at the previously active lever. The efficacy and selectivity of this stimulus to elicit responding remained unaltered throughout a 34-day phase of repeated testing as well as following the additional extended abstinence period.

In pharmacological tests, conducted in a separate group of rats, the dopamine (DA) D(1) antagonist SCH 39166 (10 microg/kg), the D(2/3) antagonist nafadotride (1 mg/kg), and the D(2/3) agonist PD 128907 (0.3 mg/kg) suppressed the cue-induced response reinstatement while the D(1) agonist SKF 81297 (1.0 mg/kg) produced a variable behavioral profile attenuating cue-induced responding in some rats while exacerbating this behavior in others. The results suggest that the motivating effects of cocaine-related stimuli are highly resistant to extinction. The undiminished efficacy of the cocaine S(+) to induce drug-seeking behavior both with repeated testing and following long-term abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in long-lasting vulnerability to relapse associated with cocaine addiction. Finally, the results support a role of DA neurotransmission in cue-induced cocaine-seeking behavior.

People like me who had no secure attachment from birth did not LEARN to pair stimuli with people.  If all sound were the same sound one would not be able to discriminate between kinds of sounds in any way.  If there were only one taste, or one color, or one temperature on the skin no value could be assigned to anything and because no distinctions could be made.  Because my mother so pervasively inhabited my space, I had no opportunity to develop any human attachments at all; certainly I was not able to develop one with her past basic survival needs – and even those were manipulated the way a Chinese mind control expert would manipulate a victim’s environment for their own ends.

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Borgland et al 2006

Abstract – San Francisco

Dopamine neurons in the

….ventral tegmental area (VTA)

represent a critical site of synaptic plasticity induced by addictive drugs.

And possibly by attachment contact with others, social support – they know how this mediates the gene for depression when children have been maltreated!

[Hypocretin (orexin) receptor 2, also known as HCRTR2, is a human gene.] – peptide hormones

Official Symbol HCRTR2 and Name: hypocretin (orexin) receptor 2 [Homo sapiens]

Other Aliases: OX2R

Other Designations: OTTHUMP00000017762; OTTHUMP00000039969; hypocretin receptor-2; orexin receptor 2

Chromosome: 6; Location: 6p12

Annotation: Chromosome 6, NC_000006.10 (55147028..55255377)

MIM: 602393

Gene ID: 3062

Summary:  HCRTR2 is a G-protein coupled receptor expressed exclusively in the brain. It has 64% identity with HCRTR1. HCRTR2 binds both orexin A and orexin B neuropeptides. HCRTR2 is involved in the central feedback mechanism that regulates feeding behaviour.

Orexin/hypocretin-containing neurons in the

lateral hypothalamus project to the VTA,

and behavioral studies have suggested that

………. orexin neurons play an important role in motivation, feeding, and adaptive behaviors.

………….However, the role of orexin [This is a peptide which causes alertness. Its absence is now thought to be the cause of narcolepsy. Orexin is also a potent regulator of the VTA] signaling in neural plasticity is poorly understood.

The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses.

Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.

And perhaps in attachment!

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Kovacs et al 1998

Abstract – Hungary

Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released at the posterior pituitary, also is released in the central nervous system (CNS).

OXT acts within the CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin was potently decreased by OXT treatment.

In relation to cocaine abuse, OXT dose-dependently decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT. OXT receptors in the CNS–mainly those located in limbic and basal forebrain structures–are responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism.

Dopaminergic neurotransmission–primarily in basal forebrain structures–is another important biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g. hypothermia-inducing effect of ethanol) also was inhibited by OXT.

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Hammock & Young 2006

Abstract – GA

Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour.

……………. the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours,

…………. role in the regulation of social bonding in monogamous rodents.

Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding.

……….The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain.

…………Comparative studies in voles [small rodent similar in appearance to a mouse] with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. …………….Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species.

…………High levels of oxytocin receptor (OTR) in the nucleus accumbens ………….and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole.

…………While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a species-specific repetitive element, or ‘microsatellite’, in the 5′ regulatory region of the gene encoding V1aR (avpr1a). ………This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles.

……….These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour.

………Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders.

In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders.

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Neumann et al 2006

Abstract – German

In response to forced swimming (FS), arginine vasopressin (AVP) is released somato-dendritically within the supraoptic nucleus (SON) and paraventricular nucleus (PVN), but not from neurohypophyseal terminals into blood. Together with AVP, oxytocin (OXT) is released within the SON and PVN.

Here, we studied the role of intra-SON and intra-PVN OXT in the regulation of local AVP release and into the blood in male rats.

……….. The results demonstrate a receptor-mediated effect of OXT within the SON and PVN on local and neurohypophyseal AVP release, which depends upon the activity conditions. Further,

while exerting an inhibitory effect on hypothalamo-pituitary-adrenal axis activity under basal conditions,

hypothalamic OXT is essential for an adequate acute ACTH response.

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Keck et al 2000

Abstract – Germany

The ageing process has been shown to have a profound impact on the ……………hypothalamo-neurohypophysial system (HNS) and the ……………….hypothalamo-pituitary-adrenocortical (HPA) axis in humans as well as in rodents.

Therefore, in this study, the intracerebral and peripheral release patterns of both vasopressin and oxytocin have been studied in aged male Wistar rats under basal conditions and in response to ethologically relevant stressors, using intracerebral microdialysis and chronic blood sampling techniques, respectively. ………Approximately a twofold higher basal release of arginine vasopressin (AVP) within the hypothalamic paraventricular nucleus (PVN), but not within the supraoptic nucleus (SON), was found in aged rats,

…………whereas basal oxytocin (OXT) release did not differ in comparison with young rats.

With increasing age the rise in intra-PVN release of both AVP and OXT was blunted in response to forced swimming [stress].

…………In contrast, the intra-SON release of AVP was unrelated to age.

Simultaneously recorded basal secretion of both AVP and OXT from the neurohypophysis into blood was increased in aged rats, with a blunted OXT response to swim stress.

……………Opposed to that, plasma AVP levels remained unchanged in both groups.

Basal plasma levels of corticotropin (ACTH) and corticosterone were elevated in aged rats,

………..whereas stress-elicited ACTH and corticosterone responses were indistinguishable.

These results indicate age-related changes in the HNS and HPA axis with an enhanced basal activity opposed to a blunted response to stressors with increasing age.

………….The increased basal release of AVP within the PVN suggests a role of intracerebral AVP in age-associated alterations of HPA axis regulation.

Is this enhanced basal activity similar to that seen in depression?

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Veenema et al 2007

Abstract – Germany

Aggression constitutes a central problem in several psychopathologies, ………….including anxiety and depression disorders and antisocial behaviors.

In particular, the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been associated with aggression-related disorders.

………………The present study assessed whether genetically determined levels of anxiety-related behavior influence the level of intermale aggression and whether this is associated with differences in neuroendocrine responsiveness and neuronal activation in the brain.

Adult male Wistar rats bred for high (HAB) or low (LAB) anxiety-related behavior were used, as well as non-selected rats (NAB) with an intermediate anxiety level. LAB residents displayed more aggressive behavior than HAB and NAB residents during the resident-intruder (RI) test.

………..Moreover, an inverse correlation was found between the level of anxiety and the level of aggression.

………….The plasma corticotropin (ACTH) response to RI-test exposure was significantly higher in LABs than in HABs and NABs, indicating that

……………. a higher level of aggression was linked to an elevated hormonal stress response.

Furthermore, LAB residents showed more neuronal activation in the parvocellular part of the hypothalamic paraventricular nucleus (PVN) than HAB residents 1 h after the RI-test.

…………. In addition, a tendency toward a higher number of c-Fos-positive cells in LABs compared with HABs was observed in the medial amygdala, hypothalamic attack area and central amygdala, areas relevant for the regulation of aggression.

…………These data demonstrate that low trait anxiety is correlated with high intermale aggression.

……….Furthermore, the increased neuronal activation of the PVN along with the higher ACTH responsiveness might underlie the display of high aggression.

That seems backwards from what I would have expected, that low anxiety is correlated with more aggression.  The lower anxiety, the higher the aggression – how does that fit with the opening statement of this abstract, that there is more aggression in anxiety disorders?

I would suppose that a lower anxiety male would be less threatened so could be more aggressive, have more confidence?  Interesting in other research noted here that in utero if the mother is stressed those infants that are genetically geared to be less anxious will come out more anxious, and those that are genetically prepared to be anxious will come out less so – and that this is in preparation to be better adapted to the harshness of the environment they are being born into.  If a mother is thus stressed, it is “obvious” to the infant that it better prepare itself for a less than optimal world.

Anxious types, to me, are what I would call the “sensitives.”  They will be more emotional, more influenced by their environment than non-anxious types.  They will display a greater tendency to react from implicit memory, the memory that is in the body rather than in consciousness.  Non-anxious types will do the same thing – and perhaps I am biased because I am an anxious type – will not be as invested in acting directly in response to the subtle nuances of their environment, especially socially.  They have less to gain by “getting along” with their peers because they are less dependent upon them for moderation of their own internal state.  These are probably more likely to be in the “avoidant” attachment style.  If they deem that emotion is going to cause them trouble, they will simply utilize “invisible” brain circuitry to make the emotions run completely out of sight.  They tend to be unreachable because of this, but for those of us, the anxious types, we also know they will never overwhelm us with their emotions.  Nor are they likely to be swayed by us.  They will simply go on about their business doing what they want to – which is usually what serves them.

The two types, on their extreme ends, will not experience their life in a body in the same way, and therefore in effect, these two groups are not even living in the same world.  Their ability to communicate with each other is very limited.  It is only on the common ground that they will be able to understand one another.  Usually this will be limited to the abilities of the non-anxious type as they are not unwilling to use empathy in the translational process of understanding another’s reality.  They do not have the ability to empathize that the anxious, sensitive types do.

I believe this is primarily because in the far reaches of empathy it is the ability to share another’s pain that matters most.  This is the only emotion that is responded to by high empathizers with an adjustment of their pupil size to match that of the person they are empathizing with.  I believe that it is the experience of painfulness that essentially governs how our hormones operate in tandem with every other system in our body.  The crux of the matter, literally and physiologically, sits squarely within the operational context of our opioid system at the center of our attachment system.

Much has been studied and written about autistic alterations in patterns regarding social connections.  I believe when science further matches our human reality it will be discovered that non-anxious types share in common a diminished response pattern in the brain regarding not only the experience of their own emotions, but hence the experience of the emotions of others.  Theirs is more of an object-filled objective world without the variations of texture that color the inner environment and therefore the interaction with the external environment that more anxious people experience.

The human race has always needed, and will continue to need, inhabitants that are geared on both ends and all along the continuum of anxiety.  All cannot go blissfully along responding mainly to the big things that concern mostly themselves.  There must be the ones that are finely tuned with concern for the small details that if left unattended to can explode into situations for which there is not simple adaptation.  There are times when attention to the details prevents disaster.  And yet as mice in the grass, the anxious detailed people have great difficulty stretching above the little things in order to see the big picture.  The non-anxious types are more likely to be soaring above than creeping timidly around below.  Yet we needed abilities that would enable us to detect both the mammoths and the medicines.  Because we are a social species, it has always been necessary to divide the labor and to divide the abilities that allow the labor to be accomplished.  There is balance and harmony in that.  Yet where we run into the greatest troubles in today’s world is by not recognizing that we are NOT all the same, and by expecting ourselves to be just like the other person, to be able to accomplish the same things, handle the same stress loads, respond the same to all situations.  THAT, my friend, is a recipe for disaster!

We do not all have the same abilities in response to our environment.  We do not have the same response-abilities.  We never have.  Just because we can stamp our lines of automobiles that look the same, or create boxes of cereal that all appear the same, does not mean that people are much like material objects in any sense of the word.  We share molecular construction with our inanimate brothers and sisters, but we are living beings operationally governed by higher rules.  And if we ignore these rules, things just plain break down – allostatic overload.

Because the non-anxious objective types are better able to negotiate their way around in this modern world primarily they have created, they also have been in a position to define what is normal and what is not, what is deviant and what is not, what is functional (as in object oriented material objects) and what is not, what is mental health and what is not.  I’m sorry, but I don’t buy this point of view.  It does not match what I know from my INSIDES about the world I live in – either inside of me or outside of me.

It bothers me that the polar caps are melting and the polar bears are vanishing.  Yes, destiny might be making way for a different life on a different kind of planet.  But where is the response-ability in all of this?  Who carries it for whom?

I am a very high anxiety person.  After 18 years of chronic, consistent and terrible abuse I would suspect my adaptational abilities saved my life.  The man that I love is a polar opposite.  I asked him today if he ever feels anxious.  He thought for a moment and said, “No.”  I suppose that was one of the vast differences between my parents, my father being low anxiety and my mother extremely high.

We are like two ends of a sound continuum, I suppose.  The bass and the sopranos.  I am coming to understand that low or high anxiety is not the same as being stressed, or not being stressed.  Each are susceptible to stress disorders, but they will probably be of a different nature.  Our sensitivities are different, and stress will cause different manifestations of ill-being, disease.

It is interesting that brain research shows that avoidant attachment people, who usually do not appear anxious, actually have very busy brain activity running in the background to keep emotions hidden.  I imagine this condition being similar to a computer’s operating system.  It can’t run without one, but we don’t see signs of it being there and are unaware of its activities.

It is probably the people dispersed all along the middle of the anxiety continuum who are better able to deal with the ups and downs of life without going off too far in either the hypo or the hyper end.

Maybe it’s like a piece of string wrapped around a bottle.  Those of us at the polar ends would end up being closest together, staring one another in the eye, nose to nose where the two ends of the string met each other.

Definitions of anxiety on the Web:

• (psychiatry) a relatively permanent state of worry and nervousness occurring in a variety of mental disorders, usually accompanied by compulsive …
• a vague unpleasant emotion that is experienced in anticipation of some (usually ill-defined) misfortune
  wordnet.princeton.edu/perl/webwn
• Anxiety is a physiological state characterized by cognitive, somatic, emotional, and behavioral components (Seligman, Walker & Rosenhan, 2001). These components combine to create the feelings that we typically recognize as fear, apprehension, or worry. …
  en.wikipedia.org/wiki/Anxiety
• Concern or solicitude respecting some thing or event, future or uncertain, which disturbs the mind, and keeps it in a state of painful uneasiness; A state of restlessness and agitation, often with general indisposition and a distressing sense of oppression at the epigastrium. –Dunglison
  en.wiktionary.org/wiki/anxiety
• A feeling of apprehension, fear, nervousness or dread accompanied by restlessness or tension.
  www.clevelandclinic.org/health/health-info/docs/3000/3006.asp
• A state of uneasiness and apprehension, generally about future uncertainties
  www.painaction.com/painaction/Glossary.aspx

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Kessler et al 2007

Abstract – Germany

Following secretion from the posterior pituitary, the neuropeptide vasopressin (AVP) stimulates the kidney to retain water, and when released centrally it can contribute to anxiety- and depression-like behaviours.

…………We hypothesized that CD1 mice bred for low trait anxiety (LAB) suffer from a deficit in AVP [vasopressin]

Both osmotically stimulated peripheral secretion and intra-paraventricular nucleus (PVN) release of AVP were found decreased in LAB animals compared with normal anxiety (NAB) or high anxiety (HAB) controls.

……….Consequently, in addition to their extreme non-anxiety, LAB mice showed signs of central diabetes insipidus (cDI), [a rare form of diabetes resulting from a deficiency of vasopressin (the pituitary hormone that regulates the kidneys);

………including increased fluid intake and reduced urine osmolality, as well as a pathological increase in plasma osmolality upon water deprivation.

……….These cDI symptoms were attenuated by administration of a selective AVP V2 receptor agonist.

A single nucleotide polymorphism (SNP) in exon 1 (C(+40)T) of the Avp gene of LAB animals causes an amino acid substitution in the signal peptide of the AVP precursor, and is likely to impair processing and trafficking of the precursor, as suggested by reduced axonal transport of AVP from the hypothalamic PVN, finally contributing to cDI symptoms and low trait anxiety.

In an F2 panel, this SNP co-segregated with fluid intake and showed a partial contribution to low anxiety-related behaviour

………….Thus, the SNP-associated deficit in plasma and central AVP contributes to signs of cDI and, at least partially, to low trait anxiety, both features being typical of LAB animals.

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Beiderbeck, Neumann & Veenema 2007

Abstract – Germany

Several studies suggest a role for arginine vasopressin (AVP), particularly in the lateral septum, in the regulation of intermale aggression

….. LAB residents showed a significantly higher level of aggression than HAB residents, as reflected by more time spent with lateral threat, offensive upright and total aggressive behaviour as well as by more attacks and a shorter attack latency.

……….Septal AVP release was significantly decreased in high-aggressive LAB males, while septal AVP release tended to increase in HAB males during resident-intruder test exposure.

……..Moreover, LAB residents showed reduced neuronal activation of the lateral septum, as indicated by fewer c-Fos-positive cells,

…………application of AVP into the septum enhanced anxiety-related behaviour on the elevated plus-maze in LAB males,

………while local administration of the V1a receptor antagonist reduced social investigation in HAB males during the resident-intruder test.

In conclusion, although AVP release patterns within the septum are dependent on the level of aggression, locally released AVP does not seem to be directly involved in the regulation of aggression, but rather modulates non-aggressive social and anxiety-related behaviours.

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Zelena et al 2006

Abstract – Hungary

Diabetes mellitus (DM), as chronic stress activates the hypothalamo-pituitary-adrenocortical axis. We examined whether arginine vasopressin (AVP) and the hypothalamic paraventricular nucleus (PVN) participate in DM-induced chronic stress symptoms.

AVP-deficient Brattleboro or PVN-lesioned Wistar rats were used with heterozygous or sham-operated controls. The rats were studied 2 wk after a single injection of streptozotocin. The appearance of DM (enhanced water consumption and blood glucose elevation) and the chronic stress-like somatic changes (body weight decrease, thymus involution, adrenal gland hypertrophy)

………were not influenced by the lack of AVP. By contrast, PVN lesion significantly attenuated DM-induced thymus involution and adrenal gland hypertrophy as well as the increase in water consumption. The corticotropin-releasing hormone mRNA in PVN was diminished by DM and elevated by the lack of AVP without interaction. DM elevated the proopiomelanocortin (POMC) mRNA in the anterior lobe of the pituitary. The lack of AVP had no effect, whereas lesioning the PVN significantly diminished the elevation. The elevated basal corticosterone plasma levels detectable in DM were influenced neither by the lack of AVP nor by lesioning the PVN. Thus the lack of AVP had no influence on DM-induced chronic stress symptoms, but lesioning the PVN attenuated part of them. However, the lack of elevation in POMC mRNA after PVN lesion, together with the maintained corticosterone elevation, suggests that direct adrenal gland activation occurs in untreated DM.

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Welt et al 2006

Abstract – Germany

We investigated the influence of a representative classical benzodiazepine on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis activity both under basal conditions and stress. Adult male Wistar rats…. Temazepam blunted the stressor exposure-induced secretion of ACTH in a dose-dependent manner.

………..Concurrently, and also in a dose-dependent manner temazepam enhanced the intra-PVN release of AVP, known to originate from magnocellular neurons of the hypothalamic neurohypophyseal system. Furthermore, temazepam did not affect the in vitro secretion of ACTH from the adenohypophyseal cells. Taken together, the results of this study suggest that temazepam modulates the central nervous regulation of the HPA axis by altering intra-PVN AVP release.

An increasingly released AVP of magnocellular origin seems to provide a negative tonus on ACTH secretion most probably via inhibiting the release of ACTH secretagogues from the median eminence into hypophyseal portal blood.

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Lim & Young 2004

Abstract – GA

Arginine vasopressin and its V1a receptor subtype (V1aR) are critical for pair bond formation between adult prairie voles.

However, it is unclear which brain circuits are involved in this vasopressin-mediated facilitation of pair bond formation. Here, we examined mating-induced Fos expression in several brain regions involved in sociosexual and reward circuitry in male prairie voles. Consistent with studies in other species, Fos expression was induced in several regions known to be involved in sociosexual behavior, namely, the medial amygdala, bed nucleus of the stria terminalis, and medial preoptic area. Fos induction also occurred in limbic and reward regions, including the ventral pallidum, nucleus accumbens, and mediodorsal thalamus (MDthal).

Next, we infused a selective V1aR antagonist into three candidate brain regions that seemed most likely involved in vasopressin-mediated pair bond formation: the ventral pallidum, medial amygdala, and MDthal. Blockade of V1aR in the ventral pallidum, but not in the medial amygdala or MDthal, prevented partner preference formation. Lastly, we demonstrated that the mating-induced Fos activation in the ventral pallidum was vasopressin-dependent, since over-expression of V1aR using viral vector gene transfer resulted in a proportionate increase in mating-induced Fos in the same region.

This is the first study to show that vasopressin neurotransmission occurs in the ventral pallidum during mating, and that V1aR activation in this region is necessary for pair bond formation in male prairie voles.

The results from this study have profound implications for the

neural circuitry underlying social attachment

and generate novel hypotheses regarding the

neural control of social behavior.

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Lim et al 2004

Abstract – GA

The molecular mechanisms underlying the evolution of complex behaviour are poorly understood. The mammalian genus Microtus provides an excellent model for investigating the evolution of social behaviour. Prairie voles (Microtus ochrogaster) exhibit a monogamous social structure in nature, whereas closely related meadow voles (Microtus pennsylvanicus) are solitary and polygamous. In male prairie voles, both vasopressin and dopamine act in the ventral forebrain to regulate selective affiliation between adult mates, known as pair bond formation,

The vasopressin V1a receptor (V1aR) is expressed at higher levels in the ventral forebrain of monogamous than in promiscuous vole species, whereas dopamine receptor distribution is relatively conserved between species. Here we substantially increase partner preference formation in the socially promiscuous meadow vole by using viral vector V1aR gene transfer into the ventral forebrain. We show that a change in the expression of a single gene in the larger context of pre-existing genetic and neural circuits can profoundly alter social behaviour, providing a potential molecular mechanism for the rapid evolution of complex social behaviour.

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Lim, Hammock & Young 2004

Abstract – GA

Arginine vasopressin modulates pairbond formation in the monogamous prairie vole (Microtus ochrogaster). Our laboratory has investigated the genetic and neural mechanisms by which vasopressin and its V1a receptor (V1aR) regulate social attachment between mates. Non-monogamous vole species show strikingly different distribution patterns of brain V1aR expression compared to monogamous species, and these patterns are thought to arise from species differences in the respective promoter sequences of the V1aR gene.

Individual differences in prairie vole V1aR patterns may also reflect individual differences in promoter sequences.

Pharmacological and genetic manipulation of the specific brain regions that express V1aR in the ‘monogamous pattern’ allows multilevel examination of the neural circuits that underlie pairbond formation in monogamous species.

……… For example, V1aR are expressed in brain regions involved in reward circuitry in monogamous vole species and have been implicated in pairbonding.

………..V1aR are also highly expressed in regions implicated in the olfactory processing of sociosexual behaviour. [being at the center of the limbic, emotional brain – from our interactions with pheromones and our avoidance of poison foods, no doubt related – if our noses were better today!!]

We hypothesize that both circuits of reward and olfactory memory underlie the cognitive mechanisms that control pairbonding.

……When used in conjunction, genetic and cellular analyses of a complex social behaviour can provide a coherent framework with which to examine the role of the vasopressin system in species evolution and neural control of behaviour.

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Phelps & Young 2003

Abstract – GA

The vasopressin V1a receptor is a gene known to be central to species differences in social behavior, including differences between the monogamous prairie vole and its promiscuous congeners.

To examine how individual differences compare with species differences, we characterize variability in the expression of the vasopressin V1a receptor (V1aR) in a large sample of wild prairie voles. We find a surprising degree of intraspecific variation in V1aR binding that does not seem attributable to experimental sources.

Most brain regions exhibit differences between upper and lower quartiles that are comparable to differences between species in this genus. Regions that are less variable have been implicated previously in regulating monogamous behaviors, suggesting that the lack of variation at these sites could reflect natural selection on mating system.

Many brain regions covary strongly. The overall pattern of covariation reflects the developmental origins of brain regions.

,,,,,,,,,,,,,,This finding suggests that shared mechanisms of transcriptional regulation may limit the patterns of gene expression.

……….Such biases may shape both the efficacy of selection and the pattern of individual and species differences.

……..Overall, our data indicate that the prairie vole would be a useful model for exploring how individual differences in gene expression influence complex social behaviors.

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Hammock et al 2005

Abstract – GA

Vasopressin regulates complex behaviors such as anxiety, parenting, social engagement and attachment and aggression in a species-specific manner.

The capacity of vasopressin to modulate these behaviors is thought to depend on the species-specific distribution patterns of vasopressin 1a receptors (V1aRs) in the brain.

There is considerable individual variation in the pattern of V1aR binding in the brains of the prairie vole species, Microtus ochrogaster. We hypothesize that this individual variability in V1aR expression levels is associated with individual variation in a polymorphic microsatellite in the 5′ regulatory region of the prairie vole v1ar gene. Additionally, we hypothesize that individual variation in V1aR expression contributes to individual variation in vasopressin-dependent behaviors.

To test these hypotheses, we first screened 20 adult male prairie voles for behavioral variation using tests that measure anxiety-related and social behaviors. We then assessed the brains of those animals for V1aR variability with receptor autoradiography and used polymerase chain reaction to genotype the same animals for the length of their 5′ microsatellite polymorphism in the v1ar gene. In this report, we describe the results of this discovery-based experimental approach to identify potential gene, brain and behavior interrelationships. The analysis reveals

that V1aR levels, in some but not all brain regions, are associated with microsatellite length and that V1aR levels in those and other brain regions correlate with anxiety-related and social behaviors.

These results generate novel hypotheses regarding neural control of anxiety-related and social behaviors and yield insight into potential mechanisms by which non-coding gene polymorphisms may influence behavioral traits.

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I never would have thought to look toward vasopressin for these implications on anxiety and social behaviors!

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Donaldson et al 2008

abstract – GA

BACKGROUND: The arginine vasopressin V1a receptor (V1aR) modulates social cognition and behavior in a wide variety of species. Variation in a repetitive microsatellite element in the 5′ flanking region of the V1aR gene (AVPR1A) in rodents has been associated with variation in brain V1aR expression and in social behavior.

In humans, the 5′ flanking region of AVPR1A contains a tandem duplication of two approximately 350 bp, microsatellite-containing elements located approximately 3.5 kb upstream of the transcription start site. The first block, referred to as DupA, contains a polymorphic (GT)25 microsatellite; the second block, DupB, has a complex (CT)4-(TT)-(CT)8-(GT)24 polymorphic motif, known as RS3. Polymorphisms in RS3 have been associated with variation in sociobehavioral traits in humans, including autism spectrum disorders. Thus, evolution of these regions may have contributed to variation in social behavior in primates. We examined the structure of these regions in six ape, six monkey, and one prosimian species. RESULTS: Both tandem repeat blocks are present upstream of the AVPR1A coding region in five of the ape species we investigated, while monkeys have only one copy of this region. As in humans, the microsatellites within DupA and DupB are polymorphic in many primate species. Furthermore, both single (lacking DupB) and duplicated alleles (containing both DupA and DupB) are present in chimpanzee (Pan troglodytes) populations with allele frequencies of 0.795 and 0.205 for the single and duplicated alleles, respectively, based on the analysis of 47 wild-caught individuals. Finally, a phylogenetic reconstruction suggests two alternate evolutionary histories for this locus. CONCLUSION: There is no obvious relationship between the presence of the RS3 duplication and social organization in primates. However, polymorphisms identified in some species may be useful in future genetic association studies. In particular, the presence of both single and duplicated alleles in chimpanzees provides a unique opportunity to assess the functional role of this duplication in contributing to variation in social behavior in primates. While our initial studies show no signs of directional selection on this locus in chimps, pharmacological and genetic association studies support a potential role for this region in influencing V1aR expression and social behavior.

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Ophir, Wolff & Phelps 2008

abstract – FL

Although prairie voles (Microtus ochrogaster) are socially monogamous, males vary in both sexual and spatial fidelity. Most males form pairbonds, cohabit with one female, and defend territories. Wandering males, in contrast, have expansive home ranges that overlap many males and females.

In the laboratory, pairing is regulated by arginine vasopressin and its predominant CNS receptor, vasopressin 1a receptor (V1aR).

We investigated individual differences in forebrain V1aR expression of male prairie voles in mixed-sex seminatural enclosures. Individual differences in V1aR were compared with space use measured by radio telemetry and paternity determined with microsatellite markers. Animals engaging in extra-pair fertilizations (EPFs) as either wanderers or paired residents overlapped significantly more in same- and opposite-sex home ranges. Surprisingly, neither social fidelity measured by space use nor sexual fidelity measured by paternity was associated with V1aR expression in the ventral pallidum (VPall) or lateral septum, areas causally related to pairbond formation. In contrast, V1aR expression in the posterior cingulate/retrosplenial cortex (PCing) and laterodorsal thalamus (LDThal), areas implicated in spatial memory, strongly covaried with space use and paternity. Animals engaging in EPFs either as wanderers or paired residents exhibited low levels of LDThal and PCing V1aR expression. Individual differences in brain and behavior parallel differences between prairie voles and promiscuous congeners. The concordance among space use, paternity, and V1aR in spatial circuits suggests a common link between the mechanisms of spatial behaviors and success at EPF. The combined data demonstrate how organismal biology can inform our understanding of individual and species differences in behavioral mechanisms.

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Pitkow et al 2001

Abstract – GA

Behaviors associated with monogamy, including pair-bond formation, are facilitated by the neuropeptide vasopressin and are prevented by a vasopressin receptor [V1a receptor (V1aR)] antagonist in the male prairie vole. The neuroanatomical distribution of V1aR dramatically differs between monogamous and nonmonogamous species. V1aR binding is denser in the ventral pallidal region of several unrelated monogamous species compared with nonmonogamous species. Because the ventral pallidum is involved in reinforcement and addiction, we hypothesize that V1aR activation in this region promotes pair-bond formation via a mechanism similar to conditioning.

Using an adeno-associated viral vector to deliver the V1aR gene, we increased the density of V1aR binding in the ventral pallial region of male prairie voles. These males exhibited

increased levels of both anxiety and affiliative behavior

compared with control males. In addition, males overexpressing the V1aR in the ventral pallidal region, but not control males, formed strong partner preferences after an overnight cohabitation, without mating, with a female.

These data demonstrate a role for

…………..ventral pallidal

V1aR in affiliation and social attachment and provide a potential molecular mechanism for species differences in social organization.

There is a link here, then – with low anxiety males showing higher aggression – higher anxiety is linked to affiliative behavior – cooperation, I guess, sustaining social attachment

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Ditzen et al 2008

Article – Switzerland

Adult attachment and social support

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I used to think that I couldn’t tell the difference between feeling pain in a present relationship and pain that comes from the past.  Now I wonder if having a severe insecure attachment disorder in the first place doesn’t carry with it a level of chronic pain that is as real and is possibly more painful when my attachment system is activated than what is going on in the relationship in the present.  That “broken” attachment system pain is not in the past, it is in the present.  So then the difficulty is still surviving the pain of the activated painful attachment system AND the pain from the relationship in the present.  This isn’t “inner child” stuff.  The attachment system is the ground zero for how my body IS in the world, every moment I am alive.

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