*Endocannabinoids, Pain, Depression and Grief

PAIN KILLERS, genetics, stress reduction, and attachment operations



Brain Substrates of Infant–Mother Attachment: Contributions of Opioids, Oxytocin, and Norepinephrine


[Oxytocin and vasopressin are intimately involved in attachment]

Hirasawa et al 2004

J Physiol. 2004 Sep 1;559(Pt 2):611-24. Epub 2004 Jul 14.


Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain.

Hirasawa M, Schwab Y, Natah S, Hillard CJ, Mackie K, Sharkey KA, Pittman QJ.

Calgary Brain Institute, Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1.

Oxytocin is released from supraoptic magnocellular neurones and is thought to act at presynaptic receptors to inhibit transmitter release. We now show that this effect is mediated by endocannabinoids, but that


nonetheless plays an important role in endocannabinoid signaling.

WIN55,212-2, a cannabinoid receptor agonist, mimicked the action of oxytocin and occluded oxytocin-induced presynaptic inhibition. The cannabinoid action is at the presynaptic terminal as shown by alteration in paired pulse ratio, a reduction in miniature EPSC frequency and immunohistochemical localization of CB1 receptors on presynaptic terminals. AM251, a CB1 receptor antagonist, blocked both the WIN55,212-2 and the oxytocin-induced presynaptic inhibition of EPSCs. Depolarization of postsynaptic magnocellular neurones (which contain fatty acid amide hydrolase, a cannabinoid catabolic enzyme) caused a transient inhibition of EPSCs that could be blocked by both the AM251 and Manning compound, an oxytocin/vasopressin receptor antagonist. This indicates that somatodendritic peptide release and action on previously identified autoreceptors facilitates the release of endocannabinoids that act as mediators of presynaptic inhibition.


Cui et al 2001

J Neurosci. 2001 Dec 15;21(24):9867-76.


Prevention of cannabinoid withdrawal syndrome by lithium: involvement of oxytocinergic neuronal activation.

Cui SS, Bowen RC, Gu GB, Hannesson DK, Yu PH, Zhang X.

Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E4.

Cannabis (i.e., marijuana and cannabinoids) is the most commonly used illicit drug in developed countries, and the lifetime prevalence of marijuana dependence is the highest of all illicit drugs in the United States. To provide clues for finding effective pharmacological treatment for cannabis-dependent patients, we examined the effects and possible mechanism of lithium administration on the cannabinoid withdrawal syndrome in rats. A systemic injection of the mood stabilizer lithium, at serum levels that were clinically relevant, prevented the cannabinoid withdrawal syndrome.

The effects of lithium were accompanied by expression of the cellular activation marker Fos proteins within most oxytocin-immunoreactive neurons and a significant increase in oxytocin mRNA expression in the hypothalamic paraventricular and supraoptic nuclei.

Lithium also produced a significant elevation of oxytocin levels in the peripheral blood. We suggest that

the effects of lithium against the cannabinoid withdrawal syndrome are mediated by oxytocinergic neuronal activation and subsequent release and action of oxytocin within the CNS.

In support of our hypothesis, we found that the effects of lithium against the cannabinoid withdrawal syndrome were antagonized by systemic preapplication of an oxytocin antagonist and mimicked by systemic or intracerebroventricular injection of oxytocin. These results demonstrate that oxytocinergic neuronal activation plays a critical role in the action of lithium against the cannabinoid withdrawal syndrome in rats, thus providing a potentially novel strategy for the treatment of cannabis dependence in humans.


McGregor, Callaghan & Hunt 2008

Br J Pharmacol. 2008 May;154(2):358-68.


From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use?

McGregor IS, Callaghan PD, Hunt GE.

School of Psychology, University of Sydney, Sydney, Australia. iain@psych.usyd.edu.au

Addictive drugs can profoundly affect social behavior both acutely and in the long-term.

Effects range from the artificial sociability imbued by various intoxicating agents to the depressed and socially withdrawn state frequently observed in chronic drug users. Understanding such effects is of great potential significance in addiction neurobiology.

In this review we focus on the ‘social neuropeptide’ oxytocin

and its possible role in acute and long-term effects

of commonly used drugs.

Oxytocin regulates social affiliation and social recognition

in many species and

modulates anxiety, mood and aggression.

Recent evidence suggests that popular party drugs such as MDMA and gamma-hydroxybutyrate (GHB) may preferentially activate brain oxytocin systems to produce their characteristic prosocial and prosexual effects.

Oxytocin interacts with the mesolimbic dopamine system

to facilitate sexual and social behavior,

and this oxytocin-dopamine interaction may also influence the acquisition and expression of drug-seeking behavior

. An increasing body of evidence from animal models suggests that even brief exposure to drugs such as MDMA, cannabinoids, methamphetamine and phencyclidine can cause long lasting deficits in social behavior. We discuss preliminary evidence that these adverse effects may reflect long-term neuroadaptations in brain oxytocin systems.   Researchers need to take into account that these systems might already have been altered during early brain formation infant development, and therefore were altered before the drug use ever began – people self medicate pre-existing faults in these systems

Laboratory studies and preliminary clinical studies also indicate that raising brain oxytocin levels may ameliorate acute drug withdrawal symptoms. It is concluded that

oxytocin may play an important, yet largely unexplored, role in drug addiction. Greater understanding of this role may ultimately lead to novel therapeutics for addiction that can improve mood and facilitate the recovery of persons with drug use disorders.


this links to oxytocin and vasopressin

McDonald et al 2008

Prog Brain Res. 2008;170:129-36.


Endogenous modulators of synaptic transmission: cannabinoid regulation in the supraoptic nucleus.

McDonald NA, Kuzmiski JB, Naderi N, Schwab Y, Pittman QJ.

Hotchkiss Brain Institute, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.

The magnocellular neurons of the

hypothalamic supraoptic nucleus (SON)

are a major source of both systemic and central release of the neurohypophyseal peptides,

oxytocin (OXT) and

arginine-vasopressin (AVP).

Both OXT and AVP are released from the somatodendritic compartment of magnocellular neurons and act within the SON to modulate the electrophysiological function of these cells.

Cannabinoids (CBs) affect hormonal output and the SON may represent a neural substrate through which CBs exert specific physiological and behavioural effects. Dynamic modulation of synaptic inputs is a fundamental mechanism through which neuronal output is controlled.

Dendritically released OXT acts on autoreceptors to generate endocannabinoids (eCBs)

…..which modify both excitatory and inhibitory inputs to OXT neurons through actions on presynaptic CB receptors.

……As such, OXT and eCBs cooperate

to shape the electrophysiological properties of magnocellular OXT neurons, regulating the physiological function of this nucleus.

Further study of eCB signaling in the SON, including its interaction with AVP neurons, promises to extend our understanding of the synaptic regulation of SON physiological function.


this links to oxytocin and vasopressin

Amico et al 2008

Prog Brain Res. 2008;170:53-64.


Oxytocin knockout mice: a model for studying stress-related and ingestive behaviours.

Amico JA, Miedlar JA, Cai HM, Vollmer RR.

Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.

Oxytocin (OXT) that is released centrally is believed to be anxiolytic and have stress-attenuating effects. Oxytocin knockout (OXTKO) mice, a genetic model of OXT deficiency, have heightened corticosterone release after acute stress and greater anxiety-related behavior in an elevated plus maze compared to wild-type (WT) mice. In the present set of experiments, we recorded the rise in body temperature, referred to as stress-induced hyperthermia (SIH), following transfer to a metabolic cage, which triggers both anxiety and corticosterone release in mice.

SIH is a marker of activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system. Because corticosterone release after acute stress is typically greater in OXTKO than in WT mice, we measured SIH as a surrogate marker of corticosterone release. Following transfer to a metabolic cage, both OXTKO and WT mice increased body temperature, but to the same degree. Pregnant mice, which are known to have blunted corticosterone release to acute stress, had attenuated SIH after transfer to a metabolic cage compared to cycling mice, but both genotypes manifested the same degree of attenuation.

In addition, we tested the effects of the cannabinoid receptor 1 (CBR1) antagonist/inverse agonist (AM251) upon feeding and SIH in OXTKO versus WT mice. CBR1 antagonists are known to diminish food intake and to enhance corticosterone both basally and following acute stress. Although AM251 blunted food intake, the effect was equivalent in both genotypes.   So that would mean that oxytocin and CBR1 did not interact?

The agent did not affect the SIH response compared to mice treated with vehicle. SIH is excellent for defining anxiolytic or blunted corticosterone responses (such as the stress hyporesponsiveness of pregnancy), but is limited in its ability to detect the heightened corticosterone responses that have been reported in OXTKO mice following exposure to psychogenic stress.

See also:

Am J Physiol Regul Integr Comp Physiol. 2005 Dec;289(6):R1798-806. Epub 2005 Sep 8.


Enhanced initial and sustained intake of sucrose solution in mice with an oxytocin gene deletion.

Amico JA, Vollmer RR, Cai HM, Miedlar JA, Rinaman L.

Department of Medicine, Univ. of Pittsburgh, Pittsburgh, PA 15261, USA. jamico@pitt.edu


Kombian et al 2002

Prog Brain Res. 2002;139:235-46.


Modulation of synaptic transmission by oxytocin and vasopressin in the supraoptic nucleus.

Kombian SB, Hirasawa M, Mouginot D, Pittman QJ.

Faculty of Pharmacy, Kuwait University, Kuwait. kombian@hsc.kuniv.edu.kw

It is now generally accepted that magnocellular neurons of the supraoptic and paraventricular nuclei release the neuropeptides oxytocin and vasopressin from their dendrites.

Peptide release from their axon terminals in the posterior pituitary and dendrites differ in dynamics suggesting that they may be independently regulated. The dendritic release of peptide within the supraoptic nucleus (SON) is an important part of its physiological function since the local peptides can regulate the electrical activity of magnocellular neurons (MCNs) which possess receptors for these peptides. This direct postsynaptic action would affect the output of peptide in the neurohypophysis. Another way that these peptides can regulate MCN activity would be to modulate afferent inputs unto themselves. Although the influence of afferent inputs (inhibitory and excitatory) on SON magnocellular neuron physiology has been extensively described in the last decade, a role for these locally released peptides on synaptic physiology of this nucleus has been difficult to show until recently, partly because of the difficulty of performing stable synaptic recordings from these cells in suitable preparations that permit extensive examination. We recently showed that under appropriate conditions, oxytocin acts as a retrograde transmitter in the SON. Oxytocin, released from the dendrites of MCNs, decreased evoked excitatory synaptic transmission by inhibiting glutamate release from the presynaptic terminals. It modulated voltage-dependent calcium channels, mainly N-type and to a lesser extent P/Q-type channels, located on glutamatergic terminals. Although evidence is less conclusive, it is possible that vasopressin has similar actions to reduce excitatory transmission.

This synaptic depressant effect of oxytocin and/or vasopressin, released from dendrites, would ensure that MCNs regulate afferent input unto themselves using their own firing rate as a gauge. Alternatively, it may only be a subset of afferent terminals that are sensitive to these peptides, thereby providing a means for the MCNs to selectively filter their afferent inputs. Indeed its specificity is partly proven by our observation that oxytocin does not affect spontaneous glutamate release, or GABA release from inhibitory terminals (Brussaard et al., 1996). Thus, the dendrites of MCNs of the supraoptic nucleus serve a dual role as both recipients of afferent input and regulators of the magnitude of afferent input, allowing them to directly participate in the shaping of their output. This adds to a rapidly growing body of evidence in support of the concept of a two-way communication between presynaptic terminals and postsynaptic dendrites, and shows the potential of this nucleus as a model to study such form of synaptic transmission.

See also:

J Neurosci. 2003 May 15;23(10):4270-7.


Vasopressin differentially modulates non-NMDA receptors in vasopressin and oxytocin neurons in the supraoptic nucleus.

Hirasawa M, Mouginot D, Kozoriz MG, Kombian SB, Pittman QJ.

Neuroscience Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, T2N 4N1 Canada. hirasawa@ucalgary.ca


Sabatier & Leng 2006

Am J Physiol Regul Integr Comp Physiol. 2006 Mar;290(3):R577-84. Epub 2005 Nov 3.


Presynaptic actions of endocannabinoids mediate alpha-MSH-induced inhibition of oxytocin cells.

Sabatier N, Leng G.

Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Bldg, George Square, Edinburgh EH8 9XD, United Kingdom. n.sabatier@ed.ac.uk

We recently showed that central injections of

alpha-melanocyte-stimulating hormone (alpha-MSH)

inhibits oxytocin cells and

reduces peripheral release of oxytocin, but

induces oxytocin release from dendrites.

Dendritic oxytocin release can be triggered by agents that mobilize intracellular calcium. Oxytocin, like alpha-MSH, mobilizes intracellular calcium stores in oxytocin cells and triggers presynaptic inhibition of afferent inputs that is

mediated by cannabinoids.

We hypothesized that this mechanism might underlie the inhibitory effects of alpha-MSH. To test this, we recorded extracellularly from identified oxytocin and vasopressin cells in the anesthetized rat supraoptic nucleus (SON). Retrodialysis of a CB1 cannabinoid receptor antagonist to the SON blocked the inhibitory effects of intracerebroventricular injections of alpha-MSH on the spontaneous activity of oxytocin cells. We then monitored synaptically mediated responses of SON cells to stimulation of the organum vasculosum of the lamina terminalis (OVLT); this evoked a mixed response comprising an inhibitory component mediated by GABA and an excitatory component mediated by glutamate, as identified by the effects of bicuculline and 6-cyano-7-nitroquinoxaline-2,3-dione applied to the SON by retrodialysis. Application of CB1 receptor agonists to the SON attenuated the excitatory effects of OVLT stimulation in both oxytocin and vasopressin cells, whereas alpha-MSH attenuated the responses of oxytocin cells only.

Thus alpha-MSH can act as a “switch“; it triggers oxytocin release centrally, but at the same time through

initiating endocannabinoid production in oxytocin cells

inhibits their electrical activity and hence, peripheral secretion


Butovsky et al 2006

Pharmacol Biochem Behav. 2005 Jun;81(2):263-84.


Endocannabinoid signaling system and brain reward: emphasis on dopamine.

Gardner EL.

Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Building C-Room 393, Baltimore, MD 21224, USA. egardner@intra.nida.nih.gov

Cannabinoids are widely abused drugs. Our goal was to identify genes modulated by Delta9-tetrahydrocannabinol (Delta9-THC) treatment. We found that chronic administration of Delta9-THC (1.5 mg/kg/day, i.p.; 7 days) to rats,

downregulates the expression of oxytocin-neurophysin (OT-NP) mRNA and of OT and oxytocin-associated NP (NPOT) immunoreactivity in nucleus accumbens (NAc)

and ventral tegmental area (VTA),

brain areas involved in reward and addiction.

Real-time PCR revealed a 60% and 53% reduction of OT-NP mRNA in NAc and VTA, respectively, under chronic treatment, while no changes were observed in NAc after 24 h. Immunohistochemistry showed a large decrease in number of OT and NPOT-stained fibers in NAc (by 59% and 52%, respectively) and VTA (by 50% and 56%, respectively). No changes in cell staining were observed in the paraventricular nucleus and supraoptic nucleus. As

OT is known to inhibit development of drug tolerance

and attenuate withdrawal symptoms, we suggest that

OT downregulation could play a role during the establishment

of the chronic effects of Delta9-THC.

Also, once these receptors are disabled social and affiliative behavior is altered – as is the emotional component of what it feels like to have the very REAL use of the oxytocin system in activation


Mackie 2006

Int J Obes (Lond). 2006 Apr;30 Suppl 1:S19-23.


Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength.

Mackie K.

Department of Anesthesiology, University of Washington School of Medicine, Seattle, WA 98195-6540, USA. kmackie@u.washington.edu

The CB1 cannabinoid receptor has attracted much recent interest because of the observation that CB1 receptor antagonists have efficacy in treating metabolic syndrome and obesity. CB1 receptors also mediate most of the psychotropic effects of Delta9-tetrahydrocannabinol (Delta9THC), the principal psychoactive component of cannabis. In addition,

they are one component of an interesting and widespread

paracrine [of or relating to a hormone or to a secretion released by (endocrine) cells into the adjacent cells or surrounding tissue rather than into the bloodstream, e.g. paracrine signaling] signaling system,

the endocannabinoid system.

The endocannabinoid system is comprised of cannabinoid receptors, endogenous cannabinoids, and the metabolic pathways responsible for their synthesis and degradation. The details of the endocannabinoid system have been most thoroughly studied in the brain. Here it has been shown to be intimately involved in several forms of neuronal plasticity. That is, activation of CB1 receptors by endocannabinoids produces either short- or long-term changes in the efficacy of synaptic transmission. The behavioral consequences of these changes are many, but some of the most striking and relevant to the current symposium are those

associated with endogenous reward and consumptive behavior.

This has to be related to learning – fundamentally – and to memory

See also:

Cannabinoid CB1 Receptor-Dependent Long Term Depression in Autaptic Excitatory Neurons.

Kellogg R, Mackie K, Straiker A.

J Neurophysiol. 2009 Jun 3. [Epub ahead of print]

PMID: 19494194 [PubMed – as supplied by publisher]

Related Articles

Interplay of the endocannabinoid system with neuropeptide Y and corticotropin-releasing factor in the goldfish forebrain.

Cottone E, Guastalla A, Pomatto V, Campantico E, Palermo F, Magni AM, Mackie K, Franzoni MF.

Ann N Y Acad Sci. 2009 Apr;1163:372-5.

PMID: 19456363 [PubMed – indexed for MEDLINE]

Related Articles

Wiring and firing neuronal networks: endocannabinoids take center stage.

Harkany T, Mackie K, Doherty P.

Curr Opin Neurobiol. 2008 Jun;18(3):338-45. Review.

PMID: 18801434 [PubMed – indexed for MEDLINE]

Related Articles

Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area.

Mátyás F, Urbán GM, Watanabe M, Mackie K, Zimmer A, Freund TF, Katona I.

Neuropharmacology. 2008 Jan;54(1):95-107. Epub 2007 Jun 22.

PMID: 17655884 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Complementary distribution of type 1 cannabinoid receptors and vesicular glutamate transporter 3 in basal forebrain suggests input-specific retrograde signalling by cholinergic neurons.

Harkany T, Härtig W, Berghuis P, Dobszay MB, Zilberter Y, Edwards RH, Mackie K, Ernfors P.

Eur J Neurosci. 2003 Oct;18(7):1979-92.

PMID: 14622230 [PubMed – indexed for MEDLINE]

Related Articles


Solinas et al 2006

J Neurochem. 2006 Jul;98(2):408-19.


Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats.

Solinas M, Justinova Z, Goldberg SR, Tanda G.

Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.

Although endogenous cannabinoid systems have been implicated in the modulation of the rewarding effects of abused drugs and food, little is known about the direct effects of endogenous ligands for cannabinoid receptors on brain reward processes. Here we show for the first time that the intravenous administration of anandamide, an endogenous ligand for cannabinoid receptors, and its longer-lasting synthetic analog methanandamide,

increase the extracellular dopamine levels in the nucleus accumbens shell

of awake, freely moving rats, an effect characteristic of most drugs abused by humans.

Anandamide produced two distinctly different effects on dopamine levels: (1) a rapid, transient increase that was blocked by the cannabinoid CB1 receptor antagonist rimonabant, but not by the vanilloid VR1 receptor antagonist capsazepine, and was magnified and prolonged by the fatty acid amide hydrolase (FAAH) enzyme inhibitor, URB597;

(2) a smaller delayed and long-lasting increase, not sensitive to CB1, VR1 or FAAH blockade. Both effects were blocked by infusing either tetrodotoxin (TTX, 1 microm) or calcium-free Ringer’s solution through the microdialysis probe, demonstrating that they were dependent on the physiologic activation of dopaminergic neurotransmission. Thus, these results indicate that


through the activation of the mesolimbic dopaminergic system, participates in the signaling

of brain reward processes.

See also:

The endogenous cannabinoid anandamide produces delta-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport.

Solinas M, Tanda G, Justinova Z, Wertheim CE, Yasar S, Piomelli D, Vadivel SK, Makriyannis A, Goldberg SR.

J Pharmacol Exp Ther. 2007 Apr;321(1):370-80. Epub 2007 Jan 8.

PMID: 17210800 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys.

Justinova Z, Solinas M, Tanda G, Redhi GH, Goldberg SR.

J Neurosci. 2005 Jun 8;25(23):5645-50.

PMID: 15944392 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site


Malone et al 2008

Neuroscience. 2008 Mar 3;152(1):265-72.


Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats.

Malone DT, Kearn CS, Chongue L, Mackie K, Taylor DA.

Department of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia. dan.malone@vcp.monash.edu.au

Rearing rats in isolation has been shown to produce behavioral and neurochemical alterations similar to those observed in psychoses such as schizophrenia.

Also, a dysregulation in both the endocannabinoid and dopaminergic systems has been implicated in schizophrenia.

The aim of this study was to determine if there are differences in CB1 receptor and fatty acid amide hydrolase (FAAH) protein expression, as well as D2 dopamine receptor expression in different brain regions in rats reared in different environmental conditions. Twenty-one-day-old male Sprague-Dawley rats were either reared in individual cages (isolated rats) or in group cages of six per cage (group-housed rats) for 8 weeks. Quantitative fluorescence immunohistochemistry was performed on brain slices using antibodies specific to the CB1 or D2 receptor, or the enzyme FAAH.

Raising rats in isolation

led to a significant decrease in CB1 receptor expression

in the caudate putamen and the amygdala,

a significant increase in FAAH expression

in the caudate putamen and the

nucleus accumbens core and shell,

and no significant change in D2 receptor expression in any region studied.

These results indicate that the endocannabinoid system is altered in an animal model of aspects of psychosis.   And also, then, in those who have suffered the effects of isolation during childhood, I would suggest – that would be me to a large extent.  This is US, rat and human, without strong and adequate social support – attachment implications here, folks!

This implies that rearing rats under different housing conditions may provide new insight into the role of the endocannabinoid system in the development of psychoses.


Djouma et al 2006

Eur J Neurosci. 2006 Jun;23(12):3319-27.


The CRF1 receptor antagonist, antalarmin, reverses isolation-induced up-regulation of dopamine D2 receptors in the amygdala and nucleus accumbens of fawn-hooded rats.

Djouma E, Card K, Lodge DJ, Lawrence AJ.

Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.

We have previously shown that Fawn-Hooded (FH)

rats reared in isolation display an anxiety-like phenotype

and an enhanced acquisition of ethanol seeking behavior. Furthermore, antalarmin, a selective corticotrophin-releasing factor type 1 (CRF1) receptor antagonist, reduces isolation-induced acquisition and maintenance of volitional ethanol consumption in this strain. The aim of this study was to investigate the ability of CRF1 receptor antagonism by antalarmin to impact upon brain chemistry in both isolated and group-housed FH rats. To achieve this, FH rats were reared, from weaning, in either group-housed or isolation-housed conditions and at 12 weeks of age were treated with antalarmin (20 mg/kg, i.p; n = 10 per group) or vehicle (1 mL/kg, i.p; n = 10 per group) bi-daily for ten consecutive days before being killed and their brains removed for neurochemical analyses. Autoradiography and in situ hybridization was employed to analyze changes in the dopaminergic and neurotrophin systems.

Isolation rearing increased dopamine D2 receptor density in the central amygdala and nucleus accumbens,

an effect reversed by antalarmin treatment.

Conversely, treatment with antalarmin had no impact upon the isolation-induced alterations of the mRNA encoding brain-derived neurotrophic factor or the TrkB receptor.

Collectively, these findings demonstrate that

multiple signaling systems

are susceptible to modulation by social isolation

and that antalarmin can reverse some, but not all,

isolation-induced alterations in brain chemistry.


Di Forti et al 2007

Curr Opin Psychiatry. 2007 May;20(3):228-34.


Cannabis use and psychiatric and cogitive disorders: the chicken or the egg?

Di Forti M, Morrison PD, Butt A, Murray RM.

Department of Psychological Medicine, Institute of Psychiatry, London, UK.

PURPOSE OF REVIEW: Cannabis is the world’s most commonly used illicit drug. In this review, we consider the recent literature on the effects of cannabis on mental health and on cognition. RECENT FINDINGS: Cannabis use in adolescence increases the risk of later schizophrenia-like psychoses, especially in genetically vulnerable individuals. Not surprisingly, patients already suffering from psychosis who use cannabis have a worse outcome than those who do not. These effects of cannabis may be consequent on its impact on the dopamine system. There is less evidence of cannabis playing an aetiological role in other mental disorders including depression, but there have been far fewer studies. Heavy cannabis use has also been shown to affect memory and learning performance, both in healthy individuals and in patients suffering from psychosis. Combined cognitive-behavioural therapy and motivational interviewing seems a promising psychological intervention to achieve a cessation of cannabis use in patients suffering from schizophrenia. SUMMARY: Further research is needed to understand the biological mechanisms underlying the effects of cannabis on mental health, but intervention strategies to help patients abstain should currently be implemented in psychiatric services, and public education campaigns should be directed at increasing awareness of the health risks of cannabis.

Linda note:  It seems obvious to me that many people who rely on pot already are hurting or have difficulties for which they are self medicating – how is it possible to know which, truly, comes first?


See also from reproductive section:

Hill, Karacabeyli & Gorzalka 2007

Psychoneuroendocrinology. 2007 May;32(4):350-7. Epub 2007 Mar 27.


Estrogen recruits the endocannabinoid system to modulate emotionality.

Hill MN, Karacabeyli ES, Gorzalka BB.

Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, Canada V6T1Z4.


Enter the search words “dopamine cannabinoid” in the pubmed database and it brings up 671 research articles.


[Considering my suspicion that drugs used during my mother’s delivery of me (most probably Twilight sleep) triggered her psychosis is related to this following article.]


Leweke & Koethe 2008

Addict Biol. 2008 Jun;13(2):264-75.


Cannabis and psychiatric disorders: it is not only addiction.

Leweke FM, Koethe D.

Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. leweke@ecnp.net

Since the discovery of the endocannabinoid system, a growing body of psychiatric research has emerged focusing on the role of this system in major psychiatric disorders like schizophrenia (SCZ), bipolar disorder (BD), major depression and anxiety disorder. Continuing in the line of earlier epidemiological studies, recent replication studies indicate that frequent cannabis use doubles the risk for psychotic symptoms and SCZ.

Further points of clinical research interest are alterations of endocannabinoids and their relation to symptoms as well as postmortem analyses of cannabinoid CB(1) receptor densities in SCZ. A possible neurobiological mechanism for the deleterious influence of cannabis use in SCZ has been suggested, involving the disruption of endogenous cannabinoid signaling and functioning. Even though the number of studies is still limited for affective and anxiety disorders, previous results suggest these diseases to be exciting objectives of cannabinoid-associated research. Therefore, it became apparent that cannabis use is not only frequent in patients suffering from BD, but that it also induces manic symptoms in this group. In addition, prior antipsychotic treatment decreased the numerical density of CB(1) immunoreactive glial cells in bipolar patients. Although the data on the influence of cannabis use on the development of major depression is controversial, cannabinoid compounds could display a new class of medication, as suggested by the antidepressive effects of the fatty acid amino hydrolase inhibitor URB597 in animal models. With numerous open questions and controversial results, further research is required to specify and extend the findings in this area, which provides a promising target for novel pharmacotherapeutic interventions.

See also:

Psychopharmacology (Berl). 2009 Jun 16. [Epub ahead of print]


The endocannabinoid system as a target for modelling psychosis.

Koethe D, Hoyer C, Leweke FM.

Central Institute of Mental Health, Ruprecht-Karls-University Heidelberg, J5, 68159, Mannheim, Germany.

INTRODUCTION: Model psychosis is characterised by experimentally induced symptoms of withdrawal from reality, frequently accompanied by perceptual disturbances, thought disorders, delusional ideas and sometimes by hallucinations. These “altered states of consciousness” provide a long-standing and valid approach to enhance our understanding of certain aspects of schizophrenia. DISCUSSION: Targeting the endocannabinoid system to investigate its involvement in the pathophysiology of schizophrenia became increasingly relevant with the discovery of this system and amounting epidemiological evidence for a deleterious influence of cannabis use on both manifestation and course of the disease. The majority of studies in the field are targeted to investigate drug effect of cannabis and cannabinoids not immediately related to psychosis. CONCLUSION: In this review, we summarise studies relevant for or designed as model psychosis experiments. Based on the data available, we examine the contribution of these studies to an improved neurobiological assessment of endocannabinoid functioning in psychosis and schizophrenia. An outline for future studies in the field and cross-links to other approaches to model psychosis is provided.

PMID: 19529920 [PubMed – as supplied by publisher]


McLaughlin et al 2007

Behav Pharmacol. 2007 Sep;18(5-6):431-8.


Local enhancement of cannabinoid CB1 receptor signalling in the dorsal hippocampus elicits an antidepressant-like effect.

McLaughlin RJ, Hill MN, Morrish AC, Gorzalka BB.

Department of Psychology, University of British Columbia, Vancouver, Canada.

Systemic administration of direct cannabinoid CB1 receptor agonists and inhibitors of the hydrolytic enzyme fatty acid amide hydrolase have been shown to elicit antidepressant effects.

Moreover, the endocannabinoid system in the hippocampus is sensitive to both chronic stress and antidepressant administration,

suggesting a potential role of this system in emotional changes associated with these regimens.

…These data indicate that

activation of CB1 receptors in the

dentate gyrus

of the hippocampus

results in an antidepressant-like response.

Collectively, these data highlight the potential importance of changes in the hippocampal endocannabinoid system following stress or antidepressant treatment with respect to the manifestation and/or treatment of depression.


Koethe et al 2007

J Neural Transm. 2007;114(8):1055-63. Epub 2007 Mar 19.


Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression.

Koethe D, Llenos IC, Dulay JR, Hoyer C, Torrey EF, Leweke FM, Weis S.

Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. koethe@ecnp.net

The human endogenous cannabinoid system is an appealing target in the investigation of psychiatric disorders. In schizophrenia, endocannabinoids and their receptors are involved in the pathology of the disease. Previous studies reported an increased radioligand binding to cannabinoid receptors 1 (CB(1)) in schizophrenia, both in the dorsolateral prefrontal cortex and in the anterior cingulate cortex (ACC). We analyzed the expression of the CB(1) receptors in the ACC at the protein level using immunohistochemistry. In a quantitative postmortem study, 60 patients suffering from schizophrenia, bipolar disorder, major depression and controls were included. Numerical densities of neurons and glial cells immunopositive for CB(1) receptors were evaluated. No evidence of an increased or decreased density of CB(1) receptor immunopositive cells in schizophrenia or bipolar disorder was found. In major depression, CB(1) receptor immunopositive glial cells in the grey matter were decreased. Furthermore, our data show that different medications have an impact on the expression of CB(1) receptors in the ACC.


Boutrel 2008

Br J Pharmacol. 2008 May;154(2):343-57. Epub 2008 Apr 14.


A neuropeptide-centric view of psychostimulant addiction.

Boutrel B.

Center for Psychiatric Neuroscience and Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Site de Cery, Prilly, Switzerland. benjamin.boutrel@chuv.ch

Drugs of abuse all share common properties classically observed in human beings and laboratory animals. They enhance neural firing and dopamine tone within the nucleus accumbens and produce progressively greater drug-induced motor responses defined as behavioural sensitization.

They produce conditioned place preference, a behavioural model of incentive motivation, which highlights the role of environmental cues in drug addiction.

They increase brain reward function as seen by a lowering of intracranial self-stimulation thresholds.

And last but not least, they are self-administered, and sometimes even abused, and can trigger reinstatement of drug-seeking behavior in animals extinguished from drug self-administration.

It has long been considered that the reinforcing properties of virtually all drugs of abuse, more specifically psychostimulants, are primarily dependent on activation of the mesolimbic dopamine system. However, recent evidence raises the

importance of dopamine-independent mechanisms in reward-related behaviors.

The overwhelming body of evidence that indicates a critical role for the mesolimbic dopamine system in the reinforcing effect of psychostimulants should not mask the key contribution of other modulatory systems in the brain. This review summarizes the complex and subtle role of several neuropeptidergic systems in various aspects of addictive behaviors observed in laboratory animals exposed to psychostimulants. A special

emphasis is given to the cannabinoid, opioid, nociceptin/orphanin FQ, corticotropin-releasing factor and hypocretin/orexin systems.

The relevance of these systems viewed as potential therapeutic targets for drug addiction is discussed in the light of their narrow pharmacological profile and their effectiveness in preventing drug addiction at doses usually not accompanied by severe side effects.


Addict Biol. 2008 Jun;13(2):225-38.


The role of CB1 receptors in psychostimulant addiction.

Wiskerke J, Pattij T, Schoffelmeer AN, De Vries TJ.

Department of Anatomy and Neurosciences, VU Medical Center, Amsterdam, The Netherlands.


Cichewicz 2004

From abstract – Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. dcichewi@hsc.vcu.du

Cannabinoids and opioids both produce analgesia

….through a G-protein-coupled mechanism

….that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord.

However, high doses of these drugs, which may be required to treat chronic, severe pain, are accompanied by undesirable side effects. Thus, a search for a better analgesic strategy led to the discovery that

……….delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, enhances the potency of opioids such as morphine in animal models.

………In addition, studies have determined that the analgesic effect of THC is, at least in part,

….mediated through delta and kappa opioid receptors,

….indicating an intimate connection between cannabinoid and opioid signaling pathways in the modulation of pain perception. [Linda note:  both of these systems are also intimately linked to the operation of our attachment system]

A host of behavioral and molecular experiments have been performed to elucidate the role of opioid receptors in cannabinoid-induced analgesia….The aim of such studies is to develop a novel analgesic regimen using low dose combinations of cannabinoids and opioids to effectively treat acute and chronic pain, especially pain that may be resistant to opioids alone.


Egashira et al 2008

Eur J Pharmacol. 2008 Jul 28;589(1-3):117-21. Epub 2008 Apr 8.


Delta(9)-tetrahydrocannabinol prolongs the immobility time in the mouse forced swim test: involvement of cannabinoid CB(1) receptor and serotonergic system.

Egashira N, Matsuda T, Koushi E, Higashihara F, Mishima K, Chidori S, Hasebe N, Iwasaki K, Nishimura R, Oishi R, Fujiwara M.

Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.

involvement of cannabinoid CB(1) receptor and serotonergic system.

In the present study, we investigated the effect of Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component of marijuana, on immobility time during the forced swim test. THC (2 and 6 mg/kg, i.p.) significantly prolonged the immobility time. …. These findings suggest that

the 5-HT(1A) receptors are involved in THC-induced enhancement of immobility.


Romero et al 1997

Brain Res Mol Brain Res. 1997 Jun;46(1-2):100-8.


Effects of chronic exposure to delta9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions.

Romero J, Garcia-Palomero E, Castro JG, Garcia-Gil L, Ramos JA, Fernandez-Ruiz JJ.

Instituto Complutense de Drogodependencias, Department of Biochemistry, Faculty of Medicine, Complutense University, Madrid, Spain.

Previous data showed the development of tolerance to a variety of pharmacological effects of plant and synthetic cannabinoids when administered chronically. This tolerance phenomenon has been related both to enhancement of cannabinoid metabolism and, in particular, to down-regulation of brain CB1 cannabinoid receptors, although this has been only demonstrated in extrapyramidal areas. In the present study, we have tested….

There were only two brain regions, the globus pallidus and the entopeduncular nucleus, where the specific binding for CB receptors was unaltered after 5 days of a daily delta9-THC administration. In addition, we have analyzed the levels of CB1 receptor mRNA in specific brain regions of animals chronically exposed to delta9-THC, in order to correlate them with changes in CB1 receptor binding. Thus, we observed a significant increase in CB1 receptor mRNA levels, but only in the striatum, with no changes in the hippocampus and cerebellum. In summary, CB1 receptor binding decreases after chronic delta9-THC exposure in most of the brain regions studied, although this was not accompanied by parallel decreases in CB receptor mRNA levels. This might indicate that the primary action of delta9-THC would be on the receptor protein itself rather than on the expression of CB1 receptor gene. In this context, the increase observed in mRNA amounts for this receptor in the striatum should be interpreted as a presumably compensatory effect to the reduction in binding levels observed in striatal outflow nuclei.


Hasanein et al 2007

CB1 receptor activation in the basolateral amygdala produces antinociception in animal models of acute and tonic nociception.

Hasanein P, Parviz M, Keshavarz M, Javanmardi K.

Clin Exp Pharmacol Physiol. 2007 May-Jun;34(5-6):439-49.

PMID: 17439413 [PubMed – indexed for MEDLINE]

Related Articles

1. Recent studies have suggested that the basolateral nucleus of the amygdala (BLA) participates in the processing of pain information,

…..especially noxious somatic information.

Cannabinoid receptors or CB1 mRNA are expressed more in the BLA than in other nuclei of the amygdala.

Thus, the aim of the present study was to examine whether CB1 receptors in the BLA may be involved in modulating acute and/or tonic nociceptive processing.

2. Adult rats were exposed to intra-BLA microinjection of the cannabinoid receptor agonist … [WIN 55,212-2 …] and subjected to the tail flick and formalin tests.

…..3. The rats demonstrated a dose-dependent increase in latency to withdraw from a thermal noxious stimulus in the tail flick test and a decrease in formalin-induced pain behaviours.

…….The antinociceptive effects of the CB1 receptor agonist WIN 55,212-2 … in both tests were attenuated in the presence of the selective CB1 receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3- carboxamide (AM251; 0.55 ng/side).

……Administration of the CB1 receptor antagonist AM251 … alone did not alter the nociceptive thresholds in either test.

…. the selective CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 1 microg/side) had no effect on the antinociception produced by WIN 55,212-2,

…….suggesting that the antinociceptive actions of WIN 55,212-2 are mediated by CB1 receptors.

The findings suggest the existence of a CB1-mediated inhibitory system in the BLA

…..that, when activated, does this activation happen naturally, or only with the application of exogenous “forces” such as a particular antagonist?

And when not activated by the antagonist, is this CB-1 system in operation and making us sensitized to feel pain?  What are the genetic variables in operation here?  Anybody know yet?  Is this system related to the “dove” hypersensitivity?

…..can diminish responsivity to acute and tonic noxious stimuli,

…..but that normally has no tonic effect on the response threshold of these stimuli.


Manning et al 2001

Abstract – West Point

J Neurosci. 2001 Oct 15;21(20):8238-46.


Reduction in opioid- and cannabinoid-induced antinociception in rhesus monkeys after bilateral lesions of the amygdaloid complex.

Manning BH, Merin NM, Meng ID, Amaral DG.

Department of Neuroscience, Merck Research Laboratories, Merck & Company, West Point, Pennsylvania 19486-0004, USA. barton_manning@merck.com

The amygdaloid complex is a prominent temporal lobe region that is associated with “emotional” information processing.

Studies in the rodent have also recently implicated the amygdala

…..in the processing and modulation of pain sensation,

……the experience of which involves a considerable emotional component in humans.

In the present study, we sought to establish the relevance of the amygdala to pain modulation in humans

…….by investigating the contribution of this region to antinociceptive processes in nonhuman primates.

Using magnetic resonance imaging guidance, the amygdaloid complex was lesioned bilaterally in six rhesus monkeys (Macaca mulatta) through microinjection of the neurotoxin ibotenic acid. This procedure resulted in substantial neuronal cell loss in all nuclear subdivisions of this structure.

……..In awake unoperated control monkeys,

…………systemic administration of the prototypical opioid morphine or the cannabinoid receptor agonist WIN55,212-2

…….produced dose-dependent antinociception

The antinociceptive effects of each drug were reversible with an appropriate antagonist.

In monkeys with bilateral amygdala lesions, however, the antinociceptive effects of each drug were significantly reduced.

These results constitute the first causal data demonstrating the necessity of neurons in a specific brain region for the full expression of opioid- and cannabinoid-induced antinociception in the primate.

………..Because our amygdala-lesioned monkeys exhibited both a reduction in antinociception and a reduction in behavioral indices of fear (Emery et al., 2001),

………..the possibility should be considered that, in the primate,

“antinociceptive circuitry” and

“fear circuitry” overlap at the level of the



Lin et al 2008

Cereb Cortex. 2009 Jan;19(1):165-75. Epub 2008 May 13.


The role of prefrontal cortex CB1 receptors in the modulation of fear memory.

Lin HC, Mao SC, Su CL, Gean PW.

Institute of Basic Medical Sciences and Department of Pharmacology, Center for Gene Regulation and Signal Transduction Research, National Cheng-Kung University, Tainan 701, Taiwan

Understanding the mechanism of how fear memory can be extinguished could provide potential therapeutic strategies for the treatment of

posttraumatic stress disorders.

Here we show that infusion of CB1 receptor antagonist into the infralimbic (IL) subregion of the medial prefrontal cortex (mPFC)

….retarded cue-alone-induced reduction of fear-potentiated startle.

………Conversely, cannabinoid agonist WIN55212-2 (WIN) facilitated the extinction.

….Unexpectedly, administration of WIN without cue-alone trials reduced startle potentiation in a dose-dependent manner.

The effect of cannabinoid agonists was mimicked by endocannabinoid uptake or fatty acid amide hydrolase inhibitors. Rats were trained with 10 conditioned stimulus (CS(+)) (yellow light)-shock pairings. Extinction training with CS(+) (yellow light)-alone but not CS(-) (blue light)-alone trials decreased fear-potentiated startle. Intra-IL infusion of WIN before CS(-)-alone trials decreased startle potentiation, suggesting that the cannabinoid agonist decreased conditioned fear irrespective of whether the rats underwent CS(+)- or CS(-)-alone trials. Cannabinoid agonists activated extracellular signal-regulated kinases (ERKs) in mPFC slices, and ERK inhibitor blocked the effect of cannabinoid agonists on fear-potentiated startle. These results suggest that

CB1 receptors

acting through the phosphorylation of ERK

are involved not only in the extinction of conditioned fear

but also in the adaptation

to aversive situations in general.


Palermo et al 2008

Mol Cell Endocrinol. 2008 Apr 16;286(1-2 Suppl 1):S52-9. Epub 2008 Feb 3.


Partial cloning of CB1 cDNA and CB1 mRNA changes in stress responses in the Solea solea.

Palermo FA, Ruggeri B, Mosconi G, Virgili M, Polzonetti-Magni AM.

Dipartimento di Scienze Morfologiche e Biochimiche Comparate, Università degli Studi di Camerino, via Gentile III da Varano, 62032 Camerino (MC), Italy.

Endogenous cannabinoids, through the

CB1 receptor, are

involved in the control of several functions including

stress responses.

The aim of this study was to investigate the presence of cannabinoid receptor CB1 in the sole ovary by partial cloning of brain CB1 cDNA; in a stress paradigm of disturbance by handling, which consisted in catching, netting and hand-sorting, changes of CB1 mRNA were related with those of proopiomelanocortin (POMC) mRNA; the trend and timing of stress responses and adaptation were monitored by measuring plasma cortisol levels. We characterized

two forms of CB1-like receptor, termed CB1A and CB1B.

The two sole CB1 (both 799bp) share 76% identity in their cDNAs, and the deduced amino acid sequences are 80% identical.

The handling stress induced a sustained increase in plasma cortisol levels 1h after the handling began and decreased to low levels 12h after initiation of handling, showing the same trend of ovarian POMC mRNA expression. In addition, while CB1A mRNA did not show any significant changes during handling stress, significantly lower levels of CB1B mRNA were found in stressed fish 1h after the beginning of handling, with CB1 expression increased 24h after stress induction, both in the ovary and brain. It can be concluded that

endocannabinoid system

is involved in the modulation of adaptive responses

to environmental conditions.


Hill et al 2008

ippocampus. 2008;18(2):221-6.


Prolonged glucocorticoid treatment decreases cannabinoid CB1 receptor density in the hippocampus.

Hill MN, Carrier EJ, Ho WS, Shi L, Patel S, Gorzalka BB, Hillard CJ.

Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.

Experimental studies indicate a


functional relationship between glucocorticoids

and the endocannabinoid system;

however, the effects of repeated glucocorticoid treatment on the endocannabinoid system have not been examined.

In this study, we … measured hippocampal cannabinoid CB(1) receptor expression and endocannabinoid content. The 21-day, but not the single, administration of corticosterone significantly reduced both the binding site density and amount of protein of the hippocampal cannabinoid CB(1) receptor without affecting affinity for the CB(1) receptor agonist, [(3)H]CP55940. With regard to

hippocampal endocannabinoid content,

acute corticosterone treatment resulted in a significant reduction

in anandamide but

did not affect 2-arachidonylglycerol,


repeated corticosterone treatment

did not alter content of either

anandamide or 2-arachidonylglycerol.

These data support the hypothesis that the

cannabinoid CB(1) receptor is under negative regulation

by glucocorticoids in the hippocampus, and suggest that

hippocampal cannabinoid CB(1) receptor signaling

could be reduced under conditions associated

with hypersecretion of glucocorticoids,

such as chronic stress.


Roche et al 2007

Abstract – Department of Pharmacology and Therapeutics, NCBES Neuroscience Cluster and Center for Pain Research, National University of Ireland, Galway, University Road, Galway, Ireland.

Eur J Neurosci. 2007 Nov;26(9):2643-53. Epub 2007 Oct 23.


The effect of CB(1) receptor antagonism in the right basolateral amygdala on conditioned fear and associated analgesia in rats.

Roche M, O’Connor E, Diskin C, Finn DP.

The endocannabinoid system

mediates analgesia expressed

following exposure to conditioned or unconditioned

aversive stimuli, and

controls the extinction of conditioned aversive behavior.

Is that all sadness is, then, a reaction to yet another aversive stimuli?  Is that all that sadness is, then – a fear in another form than what we are used to recognizing?  That doesn’t seem complete, or accurate, or correct.

The present study investigated the effects of administration of the cannabinoid(1) (CB(1)) receptor antagonist SR141716A into the right basolateral amygdala (BLA) on expression of conditioned fear, formalin-evoked nociceptive behavior, fear-conditioned analgesia and associated alterations in monoamine levels in discrete rat brain areas. Re-exposure to a context previously paired with footshock significantly reduced formalin-evoked nociceptive behavior. Intra-BLA administration of SR141716A did not attenuate fear-conditioned analgesia, but reduced formalin-evoked nociceptive behavior and attenuated the formalin-induced decrease in freezing and 22-kHz ultrasonic vocalizations in the early part of the trial.

Furthermore, intra-BLA SR141716A significantly prolonged the duration of these fear-related behaviors in fear-conditioned rats not receiving formalin. Fear-conditioned analgesia was accompanied by increased homovanillic acid (HVA) : dopamine (DA) ratio and reduced serotonin (5-HT) in the cerebellum, an effect not altered by SR141716A. SR141716A-induced analgesia was accompanied by reduced DA, increased HVA : DA ratio and reduced 5-HT levels in the cerebellum, increased hippocampal HVA levels and increased 5-hydroxyindole-3-acetic acid (5-HIAA) in the amygdaloid cortex. The SR141716A-induced prolongation of contextually induced aversive behavior was accompanied by reduced DA and 3,4-dihydroxyphenylacetic acid (DOPAC), levels in the hippocampus, and increased DA and 5-HIAA in the periaqueductal grey.

These data suggest an important role for CB(1) receptors in the right BLA in mediating short-term extinction of conditioned aversive behavior but not fear-conditioned analgesia. The results also enhance our understanding of endocannabinoid-monoamine interactions of relevance to conditioned fear and associated analgesia. This is too complicated for me to understand – don’t even know what formalin is?  But, tear induced analgesia, that’s interesting.


Lin, Mao & Gean 2006

Learn Mem. 2006 May-Jun;13(3):316-21. Epub 2006 May 16.


Effects of intra-amygdala infusion of CB1 receptor agonists on the reconsolidation of fear-potentiated startle.

Lin HC, Mao SC, Gean PW.

Institute of Basic Medical Sciences and Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan. bailu@mail.nih.gov

The cannabinoid CB1 receptor has been shown to be critically involved in the extinction of fear memory.

Systemic injection of a CB1 receptor antagonist prior to extinction training blocked extinction. Conversely, administration of the cannabinoid uptake inhibitor AM404 facilitated extinction in a dose-dependent manner.

Here we show that bilateral infusion of CB1 receptor agonists into the amygdala after memory reactivation blocked reconsolidation of fear memory measured with fear-potentiated startle.

The effect was dose-dependent and could be blocked by AM251, a specific CB1 receptor antagonist. In contrast, the effect of CB1 agonists on reconsolidation was no longer seen if memory reactivation was omitted. Concomitant with block of reconsolidation, CB1 agonist-treated animals did not exhibit shock-induced reinstatement or spontaneous recovery of fear.

The absence of recovery was not attributable to permanent damage to the amygdala in WIN-treated rats, nor did the effect result from alteration of baseline startle or shock reactivity.

These results suggest that

CB1 agonists could impair fear memory via blocking reconsolidation.


See also:

Learn Mem. 2008 Dec 2;15(12):876-84. Print 2008.


Chronic cannabinoid administration in vivo compromises extinction of fear memory.

Lin HC, Mao SC, Chen PS, Gean PW.

Institute of Basic Medical Sciences and Department of Pharmacology, Center for Gene Regulation and Signal Transduction Research, National Cheng-Kung University, Tainan, Taiwan.

Pharmacol Biochem Behav. 2005 Jun;81(2):300-18.


Cannabinoid tolerance and dependence: a review of studies in laboratory animals.

González S, Cebeira M, Fernández-Ruiz J.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain. sgrc@med.ucm.es

Br J Pharmacol. 2004 Oct;143(4):455-64. Epub 2004 Sep 15.


Changes in endocannabinoid contents in reward-related brain regions of alcohol-exposed rats, and their possible relevance to alcohol relapse.

González S, Valenti M, de Miguel R, Fezza F, Fernández-Ruiz J, Di Marzo V, Ramos JA.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Ciudad Universitaria s/n, 28040-Madrid, Spain.


Hutchison et al 2008

Arch Gen Psychiatry. 2008 Jul;65(7):841-50.


The incentive salience of alcohol: translating the effects of genetic variant in CNR1.

Hutchison KE, Haughey H, Niculescu M, Schacht J, Kaiser A, Stitzel J, Horton WJ, Filbey F.

The MIND, 1101 Yale Blvd NE, Albuquerque, NM 87131, USA. kenth@unm.edu

CONTEXT: The gene that codes for cannabinoid receptor 1 (CNR1) represents an important target for investigations designed to elucidate individual differences in the etiology of alcohol dependence. OBJECTIVE: To achieve a better understanding of the role of the CNR1 gene in the etiology and treatment of alcohol dependence. DESIGN: The present investigation spans multiple levels of analysis, including receptor binding in postmortem brain tissue, neuroimaging, human laboratory models, and analyses of treatment outcome data. RESULTS: Findings indicate that the C allele of rs2023239 is associated with greater CB1 binding in the prefrontal cortex, greater alcohol cue-elicited brain activation in the midbrain and prefrontal cortex, greater subjective reward when consuming alcohol, and more positive outcomes after treatment with a medication that targets the mesocorticolimbic neurocircuitry. In addition, there were strong correlations between cue-elicited brain activation and alcohol consumption measures in individuals with the C allele. CONCLUSION: Individuals with the

C allele may be more susceptible to changes in the mesocorticolimbic neurocircuitry that is involved in the attribution of incentive salience after repeated exposure to alcohol.


Pickel et al 2006b

J Comp Neurol. 2006 Mar 20;495(3):299-313.


Targeting dopamine D2 and cannabinoid-1 (CB1) receptors in rat nucleus accumbens.

Pickel VM, Chan J, Kearn CS, Mackie K.

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA. vpickel@mail.med.cornell.edu

The nucleus accumbens (Acb) shell and core are essential components of neural circuitry mediating the reward and motor effects produced by activation of dopamine D2 or cannabinoid-1 (CB1) receptors.

D2 receptors can form heterodimeric complexes with cannabinoid-1 (CB1) receptors and

…..are also involved in control of the availability of both dopamine and endocannabinoids.

Thus, the subcellular locations of D2 and CB1 receptors with respect to each other are implicit to their physiological actions in the Acb.

We used electron microscopic immunocytochemistry to determine these locations in the Acb shell and core of rat brain. In each region, many neuronal profiles showed endomembrane and plasmalemmal distributions of one or both receptors. Approximately one-third of the labeled profiles were somata and dendrites, some of which showed overlapping subcellular distributions of D2 and CB1 immunoreactivities. The remaining labeled profiles were small axons and axon terminals containing CB1 and/or D2 receptors.

Of the labeled terminals forming recognizable synapses, approximately 20% of those containing CB1 receptors contacted D2-labeled dendrites, while conversely, almost 15% of those containing D2 receptors contacted CB1-labeled dendrites.

These results provide the first ultrastructural evidence that D2 and CB1 receptors in the Acb shell and core have subcellular distributions supporting both intracellular associations and local involvement of D2 receptors in making available endocannabinoids that are active on CB1 receptors in synaptic neurons.

These distributions have direct relevance to the

….rewarding and euphoric

…..as well as motor effects

….produced by marijuana

…and by addictive drugs enhancing dopamine levels in the Acb.


Yamamoto & Takada 2000

Jpn J Pharmacol. 2000 Nov;84(3):229-36.


Role of cannabinoid receptor in the brain as it relates to drug reward.

Yamamoto T, Takada K.

Department of Pharmacology, Graduate school of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. yamamoto@yakuri.phar.kyushu-u.ac.jp

Understanding of cannabinoid (CB) actions has been remarkably advanced during the last decade, due mainly to the identification of the G-protein-coupled cannabinoid receptors, namely,

……..CB1 receptors that are predominantly found in the brain and

……..CB2 receptors that are exclusively found in peripheral tissues.

Endogenous ligands for these receptors have also been identified. Research to date suggests that the analgesic effect of cannabinoids and the enhancement of opioid analgesia by cannabinoids are both CB1 receptor-mediated via the activation of opioid receptors.

……….The involvement of the CB1 receptor in mediating reinforcing and physical dependence-producing effects of opioids has also been suggested, with the former being considered the result of interaction with the dopaminergic neurotransmission in the midbrain dopamine system.

However, the discriminative stimulus effects of cannabinoids have been reported to be highly specific in that the effects were not substituted by other classes of compounds including opioidergic and dopaminergic agents nor were they antagonized by antagonists of various neurotransmission systems, suggesting that the discriminative stimulus effects only involve the cannabinoid system.

Thus the cannabinoid actions appear to be classifiable into at least two kinds:

1) those mediated directly through cannabinoid receptors and

2) those mediated indirectly through other systems such as opioidergic systems.

Detailed research into these actions may help to elucidate not only the mechanisms of action of exogenous cannabinoids but also the

role of endogenous cannabinoids, especially in the brain reward system.

See also:

Crit Rev Neurobiol. 2004;16(1-2):147-58.


Cannabinoids and reward: interactions with the opioid system.

Fattore L, Cossu G, Spano MS, Deiana S, Fadda P, Scherma M, Fratta W.

Institute of Neuroscience, National Research Council CNR, Section of Cagliari, Italy.


Scherma et al 2008

Neuropharmacology. 2008 Jan;54(1):129-40. Epub 2007 Aug 19.


The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition.

Scherma M, Medalie J, Fratta W, Vadivel SK, Makriyannis A, Piomelli D, Mikics E, Haller J, Yasar S, Tanda G, Goldberg SR.

Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.

Converging evidence suggests that

….the endocannabinoid system is an important constituent

….of neuronal substrates

….involved in brain reward processes

…..and emotional responses to stress.

Here, we evaluated motivational effects of intravenously administered anandamide, an endogenous ligand for cannabinoid CB1-receptors, in Sprague-Dawley rats, using a place-conditioning procedure in which drugs abused by humans generally produce conditioned place preferences (reward). ….

When anxiety-related effects of anandamide and URB597 were evaluated in a light/dark box, both a low anandamide dose (0.3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) produced anxiolytic effects when given alone, but produced anxiogenic effects when combined. ….

additive interactions between the effects of anandamide

…..on brain reward processes

…..and on anxiety may account for its

…..aversive effects when intravenously administered during FAAH inhibition with URB597.

Totally “cooperative” processes?


Scherma et al 2008

Neuropharmacology. 2008 Jan;54(1):129-40. Epub 2007 Aug 19.


The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition.

Scherma M, Medalie J, Fratta W, Vadivel SK, Makriyannis A, Piomelli D, Mikics E, Haller J, Yasar S, Tanda G, Goldberg SR.

Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.

Converging evidence suggests that

….the endocannabinoid system is an important constituent

….of neuronal substrates

….involved in brain reward processes

…..and emotional responses to stress.

Here, we evaluated motivational effects of intravenously administered anandamide, an endogenous ligand for cannabinoid CB1-receptors, in Sprague-Dawley rats, using a place-conditioning procedure in which drugs abused by humans generally produce conditioned place preferences (reward). …

When anxiety-related effects of anandamide and URB597 were evaluated …produced anxiolytic effects when given alone, but produced anxiogenic effects when combined.

additive interactions between the effects of anandamide

…..on brain reward processes

…..and on anxiety may account for its

…..aversive effects when intravenously administered during FAAH inhibition with URB597.

Linda:  Totally “cooperative” processes?


Manning, Martin & Meng 2003

Neuroscience. 2003;120(4):1157-70.


The rodent amygdala contributes to the production of cannabinoid-induced antinociception.

Manning BH, Martin WJ, Meng ID.

Department of Neuroscience, Merck Research Laboratories, 770 Sumneytown Pike WP46-300, West Point, PA 19486-0004, USA. barton_manning@merck.com

The amygdala is a temporal lobe region that is implicated in emotional information processing.

The amygdala also is associated with the processing and modulation of pain sensation.

Recently, we demonstrated that in nonhuman primates, the amygdala is necessary for the full expression of cannabinoid-induced antinociception [Manning et al 2001].

The antinociceptive [increased tolerance for pain] effect of the cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo(1,2,3-de)-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2) was significantly reduced in rhesus monkeys with large bilateral lesions of the amygdaloid complex.  So they felt more pain

….In the present study, we investigated the contribution of the amygdala to cannabinoid-induced antinociception [an increased tolerance for pain]in the rat.

Using bilateral local microinjections of the GABA(A) receptor agonist muscimol,

……we inactivated neurons originating from the central nucleus of the amygdala (CeA) or basolateral nucleus of the amygdala (BLA).

……In rats injected with intra-CeA saline, the cannabinoid receptor agonist WIN55,212-2 produced dose-dependent antinociception

….In rats treated with intra-CeA muscimol, however, the antinociceptive effect of WIN55,212-2 was significantly reduced.

….Rats treated with intra-BLA muscimol showed no deficit in WIN55,212-2-induced antinociception.

…..The effect of CeA inactivation on WIN55,212-2-induced suppression of prolonged pain …also was tested.

…. In rats treated with intra-CeA saline, WIN55,212-2 reduced the incidence of formalin-induced nociceptive behaviors and also reduced formalin-evoked c-fos expression in both superficial and deep laminae of the spinal cord dorsal horn.

…….In rats treated with intra-CeA muscimol, however, these effects of WIN55,212-2 were significantly reduced.

The results constitute the first causal data demonstrating

….the necessity of descending pain-modulatory circuitry (of which the central nucleus of the amygdala (CeA) is a component)

….for the full expression of cannabinoid-induced antinociception in the rat.

Furthermore, the results complement previous findings suggesting an overlap in neural circuitry activated by opioids and cannabinoids.


Rubio et al 2008

Neuropharmacology. 2008 May;54(6):976-88. Epub 2008 Feb 16.


CB1 receptor blockade reduces the anxiogenic-like response and ameliorates the neurochemical imbalances associated with alcohol withdrawal in rats.

Rubio M, Fernández-Ruiz J, de Miguel R, Maestro B, Michael Walker J, Ramos JA.

Departamento de Bioquímica y Biología Molecular and Centro de Investigación biomédica en Red sobre Enfermedades Neurodegenerativas, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.

There is strong evidence that blocking CB1 receptors may reduce alcohol intake in alcohol-dependent individuals.

… male Wistar rats. Administration of rimonabant attenuated the strong anxiogenic traits of the animals that developed when regular alcohol intake was interrupted.

………This may reflect the correction of the

GABA/glutamate imbalances

developed by the animals that received rimonabant in various brain regions involved in emotional (e.g. prefrontal cortex)

and motor (e.g. caudate-putamen and globus pallidus) responses.

In addition, rimonabant also affected the dopamine deficits generated by alcohol abstinence in the amygdala and ventral-tegmental area, albeit to a lesser extent.

………However, this antagonist was unable to correct the impairment caused by alcohol abstinence in serotonin and neuropeptide Y.

The endocannabinoid activity in the brain of alcohol-abstinent rats indicated that the behavioral and neurochemical improvements caused by rimonabant were not related to the attenuation of a possible increase in this activity generated by alcohol withdrawal.

………. Conversely, the density of CB1 receptors was reduced in alcohol-abstinent animals (e.g. globus pallidus, substantia nigra),

………as were the levels of endocannabinoids and related N-acylethanolamines (e.g. amygdala, caudate-putamen).

……….Thus, rimonabant possibly enhances an endogenous response generated by interrupting the regular use of alcohol. In summary, rimonabant might attenuate withdrawal symptoms associated with alcohol abstinence,

………….an effect that was presumably due to the normalization of GABA and glutamate, and to a lesser extent, dopamine transmission in emotion- and motor-related areas.


Pu, Liu & Poo 2006

Nat Neurosci. 2006 May;9(5):605-7. Epub 2006 Apr 23.


BDNF-dependent synaptic sensitization in midbrain dopamine neurons after cocaine withdrawal.

Pu L, Liu QS, Poo MM.

Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA.

The neural mechanism underlying the relapse to drug use after drug withdrawal is largely unknown.

We found that after withdrawal from repeated cocaine exposure,

…………excitatory synapses onto dopamine neurons in the ventral tegmental area (VTA) of the rat midbrain

……….became highly susceptible to potentiation by weak presynaptic stimuli,

………an effect requiring endogenous

………..brain-derived neurotrophic factor-tyrosine kinase B (BDNF-TrkB) signaling.

……………The elevated BDNF expression in the VTA after cocaine withdrawal may prime these synapses for potentiation by cue-associated activity, triggering drug craving and relapse.


Haughey et al 2008

Addiction. 2008 Oct;103(10):1678-86. Epub 2008 Aug 14.


Marijuana withdrawal and craving: influence of the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes.

Haughey HM, Marshall E, Schacht JP, Louis A, Hutchison KE.

University of Colorado at Boulder, Boulder, CO, USA.

AIM: To examine whether withdrawal after abstinence and cue-elicited craving were associated with polymorphisms within

two genes involved in regulating the

endocannabinoid system, cannabinoid receptor 1 (CNR1) and

fatty acid amide hydrolase (FAAH).

Two single nucleotide polymorphisms (SNPs) in the CNR1 (rs2023239) and FAAH (rs324420) genes, associated previously with substance abuse and functional changes in cannabinoid regulation, were examined in a sample of daily marijuana smokers. PARTICIPANTS: Participants were 105 students at the University of Colorado, Boulder between the ages of 18 and 25 years who reported smoking marijuana daily. MEASUREMENTS: Participants were assessed once at baseline and again after 5 days of abstinence, during which they were exposed to a cue-elicited craving paradigm. Outcome measures were withdrawal and craving collected using self-reported questionnaires. In addition, urine samples were collected at baseline and on day 5 for the purposes of 11-nor-9-carboxy-Delta9-tetrahydrocannabinol (THC-COOH) metabolite analysis. FINDINGS: Between the two sessions, THC-COOH metabolite levels decreased significantly, while measures of withdrawal and craving increased significantly. The

….CNR1 SNP displayed a significant abstinence x genotype interaction on withdrawal, as well as a main effect on overall levels of craving,

…..while the FAAH SNP displayed a significant abstinence x genotype interaction on craving. CONCLUSIONS: These genetic findings may have both etiological and treatment implications. However, longitudinal studies will be needed to clarify whether these genetic variations influence the trajectory of marijuana use/dependence. The identification of underlying genetic differences in phenotypes such as craving and withdrawal may aid genetically targeted approaches to the treatment of cannabis dependence.




Garcia et al 2008

Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jan 1;32(1):140-4. Epub 2007 Aug 8.


Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus.

Garcia LS, Comim CM, Valvassori SS, Réus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries GR, Gavioli EC, Kapczinski F, Quevedo J.

Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil.

Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-d-aspartate (NMDA) receptor. Clinical findings point to a rapid onset of action for ketamine on the treatment of major depression. Considering that classic antidepressants may take long-lasting time to exhibit their main therapeutic effects, the present study aims to compare the behavioral effects and the BDNF hippocampus levels of acute administration of ketamine and imipramine in rats. To this aim, rats were acutely treated with ketamine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and animal behavioral was assessed in the forced swimming and open-field tests. Afterwards, BDNF protein hippocampal levels were assessed in imipramine- and ketamine-treated rats by ELISA-sandwich assay. We observed that ketamine at the doses of 10 and 15 mg/kg, and imipramine at 20 and 30 mg/kg reduced immobility time compared to saline group, without affecting locomotor activity. Interesting enough, acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. In conclusion, our findings suggest that the

increase of hippocampal BDNF protein levels

induced by ketamine

might be necessary to produce a rapid onset of antidepressant action


Salvadore et al 2008

Biol Psychiatry. 2009 Feb 15;65(4):289-95. Epub 2008 Sep 25.


Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine.

Salvadore G, Cornwell BR, Colon-Rosario V, Coppola R, Grillon C, Zarate CA Jr, Manji HK.

Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.

BACKGROUND: Most patients with major depressive disorder (MDD) experience a period of lengthy trial and error when trying to find optimal antidepressant treatment; identifying biomarkers that could predict response to antidepressant treatment would be of enormous benefit. We tested the hypothesis that pretreatment anterior cingulate cortex (ACC) activity could be a putative biomarker of rapid antidepressant response to ketamine, in line with previous findings that investigated the effects of conventional antidepressants. We also investigated patterns of ACC activity to rapid presentation of fearful faces compared with the normal habituation observed in healthy subjects. METHODS: We elicited ACC activity in drug-free patients with MDD (n = 11) and healthy control subjects (n = 11) by rapidly presenting fearful faces, a paradigm known to activate rostral regions of the ACC. Spatial-filtering analyses were performed on magnetoencephalographic (MEG) recordings, which offer the temporal precision necessary to estimate ACC activity elicited by the rapid presentation of stimuli. Magnetoencephalographic recordings were obtained only once for both patients and control subjects. Patients were subsequently administered a single ketamine infusion followed by assessment of depressive symptoms 4 hours later.

Although healthy subjects had decreased neuromagnetic activity in the rostral ACC across repeated exposures,

patients with MDD showed robust increases

in pretreatment ACC activity.

Notably, this increase was positively correlated with subsequent rapid antidepressant response to ketamine. Exploratory analyses showed that pretreatment amygdala activity was negatively correlated with change in depressive symptoms.

CONCLUSIONS: Pretreatment rostral ACC activation may be a useful biomarker that identifies a subgroup of patients who will respond favorably to ketamine’s antidepressant effects.

Ketamine:  A date-rape drug that can produces amnesia and blackouts


See also:

Drug Alcohol Depend. 2009 Jan 1;99(1-3):354-8. Epub 2008 Oct 14.


Effects of a short-term exposure to alcohol in rats on FAAH enzyme and CB1 receptor in different brain areas.

Rubio M, de Miguel R, Fernández-Ruiz J, Gutiérrez-López D, Carai MA, Ramos JA.

Department of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Faculty of Medicine, Complutense University, 28040 Madrid, Spain.

Feeling fear is painful!!

Reilly et al 2008

Neurosci Lett. 2008 May 30;437(2):135-8. Epub 2008 Mar 30.


Novel candidate genes identified in the brain during nociception in common carp (Cyprinus carpio) and rainbow trout (Oncorhynchus mykiss).

Reilly SC, Quinn JP, Cossins AR, Sneddon LU.

University of Liverpool, School of Biological Sciences, The BioScience Building, Liverpool L69 7ZB, UK.

Agarwal et al 2007

Nat Neurosci. 2007 Jul;10(7):870-9. Epub 2007 Jun 10.


Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors.

Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, Rubino T, Michalski CW, Marsicano G, Monory K, Mackie K, Marian C, Batkai S, Parolaro D, Fischer MJ, Reeh P, Kunos G, Kress M, Lutz B, Woolf CJ, Kuner R.

Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld, Heidelberg, 69120 Germany.

Although endocannabinoids constitute one of the

first lines of defense against pain,

the anatomical locus and the precise receptor mechanisms underlying cannabinergic modulation of pain are uncertain.

Clinical exploitation of the system is severely hindered by the cognitive deficits, memory impairment, motor disturbances and psychotropic effects resulting from the central actions of cannabinoids.

We deleted the type 1 cannabinoid receptor (CB1) specifically in nociceptive neurons localized in the peripheral nervous system of mice, preserving its expression in the CNS, and analyzed these genetically modified mice in preclinical models of inflammatory and neuropathic pain. The nociceptor-specific loss of CB1 substantially reduced the analgesia produced by local and systemic, but not intrathecal, delivery of cannabinoids. We conclude that the

contribution of CB1-type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount, which should enable the development of peripherally acting CB1 analgesic agonists without any central side effects.



Richardson et al 2008

Arthritis Res Ther. 2008;10(2):R43. Epub 2008 Apr 16.


Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis.

Richardson D, Pearson RG, Kurian N, Latif ML, Garle MJ, Barrett DA, Kendall DA, Scammell BE, Reeve AJ, Chapman V.

Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK. denise.richardson@pfizer.com

INTRODUCTION: Cannabis-based medicines have a number of therapeutic indications, including

anti-inflammatory and analgesic effects.

The endocannabinoid receptor system, including the cannabinoid receptor 1 (CB1) and receptor 2 (CB2) and the endocannabinoids, are implicated in a wide range of physiological and pathophysiological processes.

Pre-clinical and clinical studies have demonstrated that cannabis-based drugs have therapeutic potential in inflammatory diseases, including rheumatoid arthritis (RA) and multiple sclerosis. The aim of this study was to determine whether the key elements of the

endocannabinoid signalling system, which produces immunosuppression and analgesia,

are expressed in the synovia of patients with osteoarthritis (OA) or RA. …. The activity of fatty acid amide hydrolase (FAAH), the predominant catabolic endocannabinoid enzyme, was measured in synovium.

CONCLUSION: Our data predict that the cannabinoid receptor system present in the synovium may be an important therapeutic target for the treatment of pain and inflammation associated with OA and RA.

Hansson et al 2007

Neuropsychopharmacology. 2007 Jan;32(1):117-26. Epub 2006 Feb 8.


Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference.

Hansson AC, Bermúdez-Silva FJ, Malinen H, Hyytiä P, Sanchez-Vera I, Rimondini R, Rodriguez de Fonseca F, Kunos G, Sommer WH, Heilig M.

Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD 20892-1108, USA.

Endocannabinoid signaling has recently been implicated in ethanol-seeking behavior.

We analyzed the expression of endocannabinoid-related genes

……..in key brain regions

……..of reward and dependence,

…….and compared them between the alcohol-preferring AA (Alko Alcohol) and nonpreferring ANA (Alko Non-Alcohol) rat lines.

A decreased expression of fatty acid amidohydrolase (FAAH), the main endocannabinoid-degrading enzyme, was found in prefrontal cortex (PFC) of AA rats,

…….and was accompanied by decreased enzyme activity in this region.

………Binding of the endocannabinoid-cannabinoid 1 (CB1) receptor ligand (3)[H]SR141716A, and [35S]GTPgammaS incorporation stimulated by the CB1 agonist WIN 55,212-2 were downregulated in the same area.

………..Together, this suggests an overactive endocannabinoid transmission in the PFC of AA animals,

…….. and a compensatory downregulation of CB1 signaling.

The functional role of impaired FAAH function for alcohol self-administration was validated

………These results show for the first time that

………..impaired FAAH function

…………may confer a phenotype

………of high voluntary alcohol intake,

……….and point to a FAAH both as a potential susceptibility factor and a therapeutic target.


Chhatwal & Ressler 2007

Abstract – Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA.

CNS Spectr. 2007 Mar;12(3):211-20.


Modulation of fear and anxiety by the endogenous cannabinoid system.

Chhatwal JP, Ressler KJ.

The last decade has witnessed remarkable progress in the understanding of the mammalian cannabinoid system, from the cloning of the endogenous cannabinoid receptor to the discovery of new pharmacologic compounds acting on this receptor. Current and planned studies in humans include compounds with effects ranging from direct antagonists to inhibitors of reuptake and breakdown. This progress has been accompanied by a much greater understanding of the

role of the cannabinoid system

in modulating the neural circuitry that mediates

anxiety and fear responses.

This review focuses on the neural circuitry and pharmacology of the cannabinoid system as it relates to the

acquisition, expression, and extinction

of conditioned fear as a

model of human anxiety.

Preclinical studies suggest that these may provide important emerging targets for new treatments of anxiety disorders.


Moreira et al 2008

Neuropharmacology. 2008 Jan;54(1):141-50. Epub 2007 Jul 19.


Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors.

Moreira FA, Kaiser N, Monory K, Lutz B.

Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany.

Anandamide and 2-arachidonoyl glycerol, referred to as endocannabinoids (eCBs),

…..are the endogenous agonists for the cannabinoid receptor type 1 (CB1).

Several pieces of evidence support a

role for eCBs in the attenuation of anxiety-related behaviours,

although the precise mechanism has remained uncertain.

The fatty acid amid hydrolase (FAAH),

….an enzyme responsible for the degradation of eCBs,

….has emerged as a promising target for anxiety-related disorders,

…..since FAAH inhibitors

….are able to increase the levels of anandamide

….and thereby induce anxiolytic-like effects in rodents.

Linda note:  This intrigues me – sometimes I search through this research for the magic keys I hope to find, about to give up, I found this one.  Anxiety moderation – tied to cannabinoid system in the amygdala – now this.  I would instinctively rather consider treatment within the parameters of this system than in any other they are modulating with drugs at this point in time.  I think, intuitively, that research in this direction will eventually make all the other drugs they use to treat depression, PTSD, anxiety disorders of every hue and color, obsolete.

When they write about the “hawks and doves” they are writing in part about a genetic anxiety continuum – and I know that vasopressin is one of the determinates of outcome in this regard.

The present study adopted both genetic and pharmacological approaches and tested the hypothesis that FAAH-deficient (FAAH(-/-)) mice as well as C57BL/6N mice treated with an FAAH inhibitor (URB597) would express reduced anxiety-like responses.

……Furthermore, as it is known that anandamide can bind several other targets than CB1 receptors,

………..we investigated whether FAAH inhibition reduces anxiety via CB1 receptors.

FAAH(-/-) mice showed reduced anxiety

…both in the elevated plus maze and in the light-dark test.

These genotype-related differences were prevented by the CB1 receptor antagonist rimonabant (3mg/kg).

…..Moreover, URB597 (1mg/kg) induced an anxiolytic-like effect in C57BL/6N mice exposed to the elevated plus maze, which was prevented by rimonabant (3mg/kg).

…..The present work provides

genetic and pharmacological evidence supporting the inhibition of FAAH as an important mechanism for the alleviation of anxiety.

In addition, it indicates an increased activation of CB1 receptors as a mechanism underlying the effects of FAAH inhibition in two models of anxiety.


Liu et al 2007

Neurosci Lett. 2007 Mar 6;414(2):155-8. Epub 2006 Dec 15.


Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressant response in major depressive disorders.

Liu Z, Zhu F, Wang G, Xiao Z, Tang J, Liu W, Wang H, Liu H, Wang X, Wu Y, Cao Z, Li W.

Department of Psychiatry, Renmin Hospital, Wuhan University, Wuhan, PR China.

Hypothalamic-pituitary-adrenal (HPA) axis

appears to play a key role in the pathogenesis of major depressive disorders (MDD).

Treatment of certain selective serotonin reuptake inhibitors (SSRIs) has been shown to reduce the activity of corticotropin-releasing hormone (CRH) neurons and may contribute to their therapeutic action. It has been proposed that the downregulation of CRH activity is final and common step of antidepressant treatment.

In this study, we tested whether the polymorphisms of three sites (rs1876828, rs242939 and rs242941) in corticotropin-releasing hormone receptor1 (CRHR1) gene are related to 6 weeks fluoxetine antidepressant effect in 127 Han Chinese patients with MDD. The results show that

the rs242941 G/G genotype and

homozygous GAG haplotype of the three single-nucleotide polymorphisms (SNPs) are associated with fluoxetine therapeutic response in MDD patients of high-anxiety (HA).

The results support the idea that the CRHR1 gene is likely to be involved in the antidepressant response in MDD.


Papiol et al 2007

Neurosci Lett. 2007 Mar 6;414(2):155-8. Epub 2006 Dec 15.


Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressant response in major depressive disorders.

Liu Z, Zhu F, Wang G, Xiao Z, Tang J, Liu W, Wang H, Liu H, Wang X, Wu Y, Cao Z, Li W.

Department of Psychiatry, Renmin Hospital, Wuhan University, Wuhan, PR China.

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in major depression.

Normalization of HPA axis has been suggested to play a role in the mechanisms of action of antidepressants. Our aim was to investigate the

influence of genetic variants in CRHR1, CRHR2, CRH-BP and FKBP5 genes on both the vulnerability for depression and the response to antidepressant treatment.

METHODS: The sample consisted of 159 depressive outpatients and 96 healthy controls of Spanish origin. Patients were assessed for clinical features including, among others, age of onset, seasonality or suicidal behavior. The episode was treated with citalopram and followed along 12 weeks. Severity of symptoms was evaluated at the inclusion and then monthly along the follow-up using a 21-item Hamilton Depression Rating Score (HDRS). SNPs were assayed using Applied Biosystems SNaP-Shot and TaqMan technology. RESULTS:

rs110402, in CRHR1 gene, was associated with an increased risk to present a seasonal pattern and an early age of onset of the first depressive episode.

Allele G carriers of rs2270007 of CRHR2 gene, showed a worse overall response to citalopram along time of follow-up (Genotype effect F=7.45, P=0.007).

G allele carriers showed 2.93 increased risk (95% CI [1.24-6.90]) for non-responding at 4th week to citalopram treatment (chi(2)=7.59, df=1, P=0.006). LIMITATIONS: On the light of the moderate sample size, associations based on the mentioned polymorphisms need to be considered with caution and require further replication studies in other samples. CONCLUSIONS:

Variability at genes encoding proteins with a pivotal role in HPA axis regulation seems to influence

i) the expression of severity variables of the depressive spectrum including early age of onset or a seasonal pattern and

ii) the interindividual variation in clinical response to SSRI antidepressants


Please refer to the related section on FEAR.  It directly relates to the following article.


Lafenetre, Chaouloff & Marsicano 2007

Abstract – Research Centre INSERM U862, AVENIR Team Molecular Mechanisms of Behavioural Adaptation, 146 rue Léo Saignat, 33700 Bordeaux, France.

Pharmacol Res. 2007 Nov;56(5):367-81. Epub 2007 Sep 8.


The endocannabinoid system in the processing of anxiety and fear and how CB1 receptors may modulate fear extinction.

Lafenêtre P, Chaouloff F, Marsicano G.

The endocannabinoid system recently emerged as an important modulator of many neuronal functions. Among them, the

control of anxiety and acquired fear

represents nowadays one of the most interesting fields of research. Despite contrasting results obtained by the use of cannabinoid receptor agonists in experimental animals, there is growing evidence that the

physiological activation of the endocannabinoid system plays a central role in the control of basal anxiety levels and in the modulation of fear responses.

This review will summarize recent data on the

role of the endocannabinoid system in most commonly used tests of anxiety and in the processing of acquired fear, with particular attention to its involvement in fear extinction.

Finally, a neurobiological model possibly able to implement the role of the endocannabinoid system in these processes will be proposed.


Lutz 2007

Abstract – Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany. blutz@uni-mainz.de

The endocannabinoid system and extinction learning.

Lutz B.

Mol Neurobiol. 2007 Aug;36(1):92-101. Epub 2007 Aug 17. Review.

PMID: 17952654 [PubMed – indexed for MEDLINE]

Related Articles

The endocannabinoid system

has emerged as a versatile neuromodulatory system,

implicated in a plethora

of physiological and pathophysiological processes.

Cannabinoid receptor type 1 (CB1 receptor) and endocannabinoids are widely distributed in the brain. Their roles in learning and memory have been well documented, using rodents in various memory tests. Depending on the test,

the endocannabinoid system is required in the acquisition and/or extinction of memory.

In particular, the

activation of CB1 receptor-mediated signaling

is centrally involved in the facilitation of behavioral adaptation

after the acquisition of aversive memories.

Sure sounds like a PTSD candidate to me.  Also, nobody ever mentions sadness and grief with depression or PTSD as being as

Real and legitimate reaction as any

Fear could be from some aversive experience

As several human psychiatric disorders, such as phobia, generalized anxiety disorders, and posttraumatic stress disorder (PTSD) appear to involve aberrant memory processing and impaired adaptation to changed environmental conditions,

the hope has been fuelled that the endocannabinoid system might be a valuable therapeutic target for the treatment of these disorders. This review summarizes the current data on the role of the endocannabinoid system in the modulation of extinction learning. 


See also:

The endogenous cannabinoid system controls extinction of aversive memories.

Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz B.

Nature. 2002 Aug 1;418(6897):530-4.

PMID: 12152079 [PubMed – indexed for MEDLINE]

Related Articles


Gerald et al 2008

From abstract – Chemistry Department, North Carolina Central University, Durham, NC 27707, USA.

RATIONALE: Endocannabinoid, opioid, and dopamine systems

….interact to exhibit cannabinoid receptor neuromodulation

…..of opioid peptides and D(4) dopamine receptor gene expression

…. in CB(1)-cannabinoid-deficient mouse striatum.

CONCLUSIONS: Greater striatal expression is genotype-dependent in females (opioid-peptides, D(3), D(4), D(5))

….and genotype-independent in both females (PPENK, mu-OR, D(4)) and old males (PPDYN, delta-OR, D(2), D(3), D(4)).


Romanelli et al 2005

nvolvement of the cannabinoid CB1 receptor in the opioid inhibition of the response to cholecystokinin and acute withdrawal response.

Romanelli L, Palmery M, Tucci P, Amico MC, Morrone LA, Valeri P.

Neurotoxicology. 2005 Oct;26(5):819-27.

PMID: 15913779 [PubMed – indexed for MEDLINE]

Related Articles

Inhibitory control of the acute mu-withdrawal response by indirectly activated adenosine A1 and kappa-opioid systems in the Guinea-pig ileum; reversal by cholecystokinin.

Romanelli L, Morrone LA, Amico MC, Palmery M, Tucci P, Valeri P.

Neurotoxicology. 2005 Oct;26(5):829-39.

PMID: 15894374 [PubMed – indexed for MEDLINE]

Related Articles

Numerous recent studies have reported major functional interactions between cannabinoid and opioid systems. These interactions can be studied in the myenteric plexus-longitudinal muscle isolated preparations. We had previously shown that in the guinea-pig ileum (GPI), the opioid acute withdrawal response is under the inhibitory control of several systems; mu-opioid agonist exposure indirectly activates the kappa-opioid system; conversely, exposure to a kappa-opioid agonist indirectly activates the mu-system; the indirectly activated opioid system inhibits the withdrawal response.

The adenosine A1 system is also indirectly activated by opioids and it inhibits the withdrawal response. ….

These results show that opioid exposure may also activate the cannabinoid CB1 system, which leads to an inhibition of the opioid acute withdrawal response. This phenomenon and the antagonistic effect of SR on the opioid-induced inhibition of the response to CCK-8 suggest that reciprocal interaction between opioid and cannabinoid systems are operating in the enteric nervous system.


A pubmed database search for “opioid cannabinoid” brings up 832 articles!  Both of these systems are intimately tied to our attachment systems.


Robledo et al 2008

Addict Biol. 2008 Jun;13(2):213-24.


Advances in the field of cannabinoid–opioid cross-talk.

Robledo P, Berrendero F, Ozaita A, Maldonado R.

Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Spain

A remarkable amount of literature has been generated demonstrating the functional similarities between the endogenous opioid and cannabinoid systems.

Anatomical, biochemical and molecular data support the

existence of reciprocal interactions between these two systems

related to several pharmacological responses including reward, cognitive effects, and the development of tolerance and dependence.

However, the assessment of the bidirectionality of these effects has been difficult due to their variety and complexity.

Reciprocal interactions have been well established for the development of physical dependence.

…………Cross-tolerance and cross-sensitization, although not always bidirectional, are also supported by a number of evidence, while less data have been gathered regarding the relationship of these systems in cognition and emotion. Nevertheless, the most recent advances in cannabinoid-opioid cross-modulation have been made in the area of drug craving and relapse processes. The present review is focused on the latest developments in the cannabinoid-opioid cross-modulation of their behavioural effects and the possible neurobiological substrates involved.


See also:

Pharmacol Biochem Behav. 2005 Jun;81(2):343-59.


Endocannabinoid system and opioid addiction: behavioural aspects.

Fattore L, Deiana S, Spano SM, Cossu G, Fadda P, Scherma M, Fratta W.

Institute of Neuroscience, National Research Council CNR, Section of Cagliari, Italy.

Pharmacol Biochem Behav. 2005 Jun;81(2):360-8.


Molecular and cellular basis of cannabinoid and opioid interactions.

Viganò D, Rubino T, Parolaro D.

DBSF, Center of Neuroscience, University of Insubria, via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy.

Crit Rev Neurobiol. 2004;16(1-2):147-58.


Cannabinoids and reward: interactions with the opioid system.

Fattore L, Cossu G, Spano MS, Deiana S, Fadda P, Scherma M, Fratta W.

Institute of Neuroscience, National Research Council CNR, Section of Cagliari, Italy.

Drug News Perspect. 2008 Apr;21(3):149-57.


The role of the endogenous cannabinoid system in drug addiction.

Parolaro D, Rubino T.

DBSF and Neuroscience Center, University of Insubria, Busto Arsizio, Italy. daniela.parolaro@uninsubria.it

Life Sci. 2008 Jun 6;82(23-24):1175-81. Epub 2008 Apr 6.


Involvement of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala in anxiety-related behavior.

Zarrindast MR, Babapoor-Farrokhran S, Babapoor-Farrokhran S, Rezayof A.

Department of Pharmacology, School of Medicine, Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran. zarinmr@ams.ac.ir

Behav Pharmacol. 2008 Oct;19(7):716-23.


Cannabinoid CB1 receptors of the rat central amygdala mediate anxiety-like behavior: interaction with the opioid system.

Zarrindast MR, Sarahroodi S, Arzi A, Khodayar MJ, Taheri-Shalmani S, Rezayof A.

Department of Pharmacology, School of Medicine and Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran. zarinmr@ams.ac.ir


Paldyova et al 2007

Acta Biol Hung. 2007;58 Suppl:113-29.


Altered gene expression and functional activity of opioid receptors in the cerebellum of CB1 cannabinoid receptor knockout mice after acute treatments with cannabinoids.

Páldyová E, Bereczki E, Sántha M, Wenger T, Borsodi A, Benyhe S.

Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.

Numerous studies have shown functional links between the cannabinoid and opioid systems.

The goal of this study was to evaluate whether acute treatments by endogenous cannabinoid agonist, selective CB1 or CB2 receptor antagonists modulate the expression of mu- (MOR) and delta- (DOR) opioid receptor mRNA levels and functional activity in the cerebellum of transgenic mice deficient in the CB1 type of cannabis receptors. We examined the effect of noladin ether (endogenous cannabinoid agonist) pretreatment……. Taken together, these results indicate that acute treatment with cannabinoids causes alterations in MOR and DOR mRNA expression and functional activity in the cerebella of wild-type and CB1 knockout mice indicating

indirect interactions

between these two signaling systems.

[opioid and cannabinoid]


Canals & Milligan 2008

J Biol Chem. 2008 Apr 25;283(17):11424-34. Epub 2008 Mar 4.


Constitutive activity of the cannabinoid CB1 receptor regulates the function of co-expressed Mu opioid receptors.

Canals M, Milligan G.

Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.

The human mu opioid receptor was expressed stably in Flp-In T-REx HEK293 cells. Occupancy by the agonist DAMGO (Tyr-d-Ala-Gly-N-methyl-Phe-Gly-ol) resulted in phosphorylation of the ERK1/2 MAP kinases, which was blocked by the opioid antagonist naloxone but not the cannabinoid CB1 receptor inverse agonist SR141716A. Expression of the human cannabinoid CB1 receptor in these cells ….

it is the constitutive activity inherent in the cannabinoid CB1 receptor that reduces the capacity of co-expressed mu opioid receptor to function.

So the cannabinoid CB1 receptor has an inherent “constitutive activity” – like it inherently is part of “the group?”  Being a constituent?  Implying influence, certainly, but also cooperative characteristics?



Eur Neuropsychopharmacol. 2008 Jul;18(7):519-30. Epub 2008 Apr 22.


Cannabinoid and opioid modulation of social play behavior in adolescent rats: differential behavioral mechanisms.

Trezza V, Vanderschuren LJ.

Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands.

We have recently shown that the pharmacological mechanisms through which cannabinoid and opioid drugs influence social play behavior in adolescent rats can be partially dissociated. Here, we characterize the effects of the direct cannabinoid agonist WIN55,212-2, the indirect cannabinoid agonist URB597 and the opioid agonist morphine on social play at the behavioral level. By treating either one or both partners of the test dyad, we show that these drugs differentially affect play solicitation and play responsiveness. By testing these drugs in animals which were either familiar or unfamiliar to the test cage, we show that environmental factors differentially modulate the effects of cannabinoid and opioid drugs on social play. These results support and extend our previous findings suggesting that, although cannabinoid and opioid systems interact in the modulation of social play behavior in adolescent rats, they do so through partially dissociable behavioral and pharmacological mechanisms.

PMID: 18434104 [PubMed – indexed for MEDLINE


Welch & Eads 1999

Brain Res. 1999 Nov 27;848(1-2):183-90.


Synergistic interactions of endogenous opioids and cannabinoid systems.

Welch SP, Eads M.

Department of Pharmacology and Toxicology, Box 980613, Virginia Commonwealth University, Richmond, VA 23298-0613, USA. S.Welch@hsc.vcu.edu

We hypothesize the existence

…..of a new CB receptor

….differentially linked to endogenous opioid systems

……based upon data showing the stereoselectivity of endogenous opioid release. Such a receptor, due to the release of endogenous opioids, may have significant impact upon the clinical development of cannabinoid/opioid combinations for the treatment of a variety of types of pain in humans.


Chakrabarti et al 2006

Abstract – Autism Research Centre, Douglas House, 18 B, Trumpington Road, Cambridge CB2 2AH, UK. bc249@cam.ac.uk

Happy facial expressions

are innate social rewards

and evoke a response in the striatum,

a region known for its role in reward processing in rats, primates and humans.

The cannabinoid receptor 1 (CNR1) is the best-characterized molecule of the endocannabinoid system, involved in processing rewards.

We hypothesized that genetic variation in human CNR1 gene would predict differences in the striatal response to happy faces. In a 3T functional magnetic resonance imaging (fMRI) scanning study on 19 Caucasian volunteers, we report that four single nucleotide polymorphisms (SNPs) in the CNR1 locus modulate differential striatal response to happy but not to disgust faces.

This suggests a role for the variations of the

CNR1 gene in underlying social reward responsivity.

Future studies should aim to replicate this finding with a balanced design in a larger sample, but these preliminary results suggest neural responsivity to emotional and socially rewarding stimuli varies as a function of CNR1 genotype. This has implications for medical conditions involving hypo-responsivity to emotional and social stimuli, such as autism.

I would think it might also somehow relate to hyper-responsivity in some way, also.


The following research is about the striatum brain region – which is impacted by our cannabinoid system as mentioned above, but is not specifically related to cannabinoid research – though regulation of the stress response is cannabinoid related

Choi et al 2008

From abstract – Neuroscience Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.

The bed nucleus of the stria terminalis (BST)

plays a prominent role in brain integration

of acute responses to stressful stimuli. Does not say

in response to the experience itself, only to the response!?

This study tests the hypothesis that the BST plays a complementary role in regulation of physiological changes associated with chronic stress exposure.

Male Sprague-Dawley rats received bilateral ibotenate lesions or sham lesions of the posterior medial region of the BST (BSTpm), an area known to be involved in inhibition of HPA axis responses to acute stress. Chronic stress was induced by 14-day exposure to twice daily stressors in an unpredictable sequence (chronic variable stress, CVS). In the morning after the end of CVS, stressed and non-stressed controls were exposed to a novel restraint stress challenge. As previously documented, CVS caused adrenal hypertrophy, thymic involution, and attenuated body weight gain. None of these endpoints were affected by BSTpm lesions. Chronic stress exposure facilitated plasma corticosterone responses to the novel restraint stress and elevated CRH mRNA. In both groups?  Doesn’t say

… Collectively these data confirm that the posterior medial region of the BST (BSTpm markedly inhibits HPA responses to acute stress, but do not strongly support an additional role for this region in limiting HPA axis responses to chronic drive. The data

further suggest that

acute versus chronic stress integration

are subserved by different brain circuitry.


Rademacher & Hillard 2007

Abstract – Medical College of Wisconsin, Department of Pharmacology and Toxicology, 8701 Watertown Plank Road, Milwaukee, WI 53226 USA. david.rademacher@rosalindfranklin.edu

Article:  Interactions between endocannabinoids and stress-induced decreased sensitivity to natural reward.

Since endocannabinoids

modulate reward processing and the stress response,

we tested the hypothesis that endocannabinoids regulate stress-induced decreased sensitivity to natural reward.

Restraint was used to produce stress-induced reductions in sucrose consumption and preference in male mice. Central cannabinoid receptor (CB(1)) signaling was modulated pharmacologically prior to the application of stress. The preference for sucrose over water was significantly decreased in mice exposed to restraint. Treatment of mice with a cannabinoid receptor agonist …[demonstrated] a tonically active, stress-inhibitory role for the CB(1) receptor. ….. These data suggest that on day 10, endocannabinoid signaling is maximally activated and essential for reward sensitivity. The findings of the present study indicate that the

CB(1)/endocannabinoid signaling system

is an important allostatic mediator

that both modulates the responses of mice to stress

and is itself modulated by stress.


Patel, Cravatt & Hillard 2005

From abstract – Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Article title:  Synergistic interactions between cannabinoids and environmental stress in the activation of the central amygdala.

Anxiety and panic are the most common adverse effects of cannabis intoxication; reactions potentiated by stress. Data suggest that cannabinoid (CB1) receptor modulation of amygdalar activity contributes to these phenomena.

… we tested the hypothesis that environmental stress and CB1 cannabinoid receptor activity interact in the regulation of amygdalar activation in male mice.

… These data suggest the CeA [area of the amygdala brain region] is an important neural substrate subserving the interactions between cannabinoids and environmental stress, and could be relevant to understanding the context-dependent emotional and affective changes induced by marijuana intoxication and the role of endocannabinoid signaling in the modulation of amygdalar activity.


Agrawal et al 2008

Arch Gen Psychiatry. 2008 Jun;65(6):713-21.


An autosomal linkage scan for cannabis use disorders in the nicotine addiction genetics project.

Agrawal A, Pergadia ML, Saccone SF, Lynskey MT, Wang JC, Martin NG, Statham D, Henders A, Campbell M, Garcia R, Broms U, Todd RD, Goate AM, Rice J, Kaprio J, Heath AC, Montgomery GW, Madden PA.

Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8134, St Louis, MO 63110, USA. arpana@wustl.edu

CONTEXT: Despite accumulating evidence that there is a genetic basis for cannabis use disorders (ie, abuse and dependence), few studies have identified genomic regions that may harbor biological risk and protective factors. OBJECTIVE: To conduct autosomal linkage analyses that identify genomic regions that may harbor genes conferring a vulnerability to cannabis use disorders. DESIGN: In 289 Australian families who participated in the Nicotine Addiction Genetics Project, 423 autosomal markers were genotyped. Families were ascertained for heavy cigarette smoking. Linkage was conducted for DSM-IV cannabis dependence and for a novel factor score representing problems with cannabis use, including occurrence of 3 of 4 abuse criteria (excluding legal problems) and 6 DSM-IV dependence criteria. RESULTS: A maximum logarithm of odds (LOD) of 3.36 was noted for the cannabis problems factor score on chromosome arm 1p. An LOD of 2.2 was noted on chromosome 4 in the region of the gamma-aminobutyric acid type A gene cluster, including GABRA2, which has been implicated in drug use disorders. For DSM-IV cannabis dependence, a modest LOD score on chromosome 6 (1.42) near cannabinoid receptor 1 (CNR1) was identified. In addition, support for an elevation on chromosome 3, identified in prior independent studies, was noted for the factor score and cannabis dependence (LOD, 1.4). CONCLUSIONS: Genes such as ELTD1 on chromosome 1, in addition to genes on chromosomes 4 (eg, GABRA2) and 6 (eg, CNR1), may be associated with the genetic risk for cannabis use disorders. We introduce a novel quantitative phenotype, a cannabis problems factor score composed of DSM-IV abuse and dependence criteria, that may be useful for future linkage and association studies.


See also:

Neuropharmacology. 2009;56 Suppl 1:235-43. Epub 2008 Jul 19.


The endocannabinoid system as a target for the treatment of cannabis dependence.

Clapper JR, Mangieri RA, Piomelli D.

Department of Pharmacology, University of California, Irvine 3101 Gillespie NRF, Irvine, CA 92697, USA


D’Souza et al 2008

Neuropsychopharmacology. 2008 Sep;33(10):2505-16. Epub 2008 Jan 9.


Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis.

D’Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, Perry E, Krystal J.

Schizophrenia Biological Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USA. deepak.dsouza@yale.edu

Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis.

Delta-9-Tetrahydrocannabinol (Delta-9-THC) the principal active ingredient of cannabis has been shown to

….induce psychotomimetic and amnestic effects in healthy individuals.

Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Delta-9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous Delta-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. Delta-9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of ‘high’; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of Delta-9-THC but not to its euphoric effects.

….Frequent users also had lower prolactin levels. These data suggest that

frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.


Mackie 2008

Mol Cell Endocrinol. 2008 Apr 16;286(1-2 Suppl 1):S60-5. Epub 2008 Feb 6.


Signaling via CNS cannabinoid receptors.

Mackie K.

Department of Psychological and Brain Sciences, Indiana University, 1101 E. 10th St., Bloomington, IN 47401, USA. kmackie@indiana.edu

Because of the prominent psychoactive effects of cannabis and its preparations, much research has focused on the actions of cannabinoids, the primary psychoactive components of cannabis, on neuronal function.

A convergence of research has identified

(1) cannabinoid receptors,

2) endogenous compounds that activate these receptors (endocannabinoids), and

(3) drugs that interact with these receptors and the proteins that synthesize and degrade the endocannabinoids.

This review will first consider how endogenous cannabinoids signal through cannabinoid receptors and the various forms of synaptic plasticity mediated by endocannabinoids.

Next the interactions between exogenous cannabinoids such as Delta9-tetrahydrocannabinol and endocannabinoids and endocannabinoid-mediated plasticity will be examined.

Finally, a model will be presented that can explain the prominent psychoactivity of these plant-derived cannabinoids.


See also:

Neuroscience. 2004;127(1):101-12.


Compartment-specific localization of cannabinoid 1 (CB1) and mu-opioid receptors in rat nucleus accumbens.

Pickel VM, Chan J, Kash TL, Rodríguez JJ, MacKie K.

Department of Neurology and Neuroscience, Cornell University Medical College, 411 East 69th Street, Room KB-410, New York, NY 10021, USA. vpickel@mail.med.cornell.edu


Cooper & Haney 2008

Addict Biol. 2008 Jun;13(2):188-95. Epub 2008 Feb 14.


Cannabis reinforcement and dependence: role of the cannabinoid CB1 receptor.

Cooper ZD, Haney M.

Division on Substance Abuse, New York State Psychiatric Institute, Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA

Awareness of cannabis dependence as a clinically relevant issue has grown in recent years. Clinical and laboratory studies demonstrate that chronic marijuana smokers can experience withdrawal symptoms upon cessation of marijuana smoking and have difficulty abstaining from marijuana use. This paper will review data implicating the cannabinoid CB1 receptor in regulating the behavioral effects of Delta(9)-tetrahydrocannobinol (THC), the primary psychoactive component of cannabis, across a range of species. The behavioral effects that will be discussed include those that directly contribute to the maintenance of chronic marijuana smoking, such as reward, subjective effects, and the positive and negative reinforcing effects of marijuana, THC and synthetic cannabinoids. The role of the CB1 receptor in the development of marijuana dependence and expression of withdrawal will also be discussed. Lastly, treatment options that may alleviate withdrawal symptoms and promote marijuana abstinence will be considered.

See also:

Int Rev Psychiatry. 2009 Apr;21(2):104-12.


Actions of delta-9-tetrahydrocannabinol in cannabis: relation to use, abuse, dependence.

Cooper ZD, Haney M.

Division on Substance Abuse, New York Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.

Cannabis use disorders have been recently identified as a relevant clinical issue: a subset of cannabis smokers seeks treatment for their cannabis use, yet few succeed in maintaining long-term abstinence. The rewarding and positive reinforcing effects of the primary psychoactive component of smoked cannabis, delta-9-tetrahydrocannabinol (THC) are mediated by the cannabinoid CB1 receptor. The CB1 receptor has also been shown to mediate cannabinoid dependence and expression of withdrawal upon cessation of drug administration, a phenomenon verified across species. This paper will review findings implicating the CB1 receptor in the behavioural effects of exogenous cannabinoids with a focus on cannabinoid dependence and reinforcement, factors that contribute to the maintenance of chronic cannabis smoking despite negative consequences. Opioidergic modulation of these effects is also discussed.


Barr et al 2008

Arch Gen Psychiatry. 2008 Aug;65(8):934-44.


CRH haplotype as a factor influencing cerebrospinal fluid levels of corticotropin-releasing hormone, hypothalamic-pituitary-adrenal axis activity, temperament, and alcohol consumption in rhesus macaques.

Barr CS, Dvoskin RL, Yuan Q, Lipsky RH, Gupte M, Hu X, Zhou Z, Schwandt ML, Lindell SG, McKee M, Becker ML, Kling MA, Gold PW, Higley D, Heilig M, Suomi SJ, Goldman D.

Laboratory of Clinical Studies, Primate Section, National Institute on Alcohol Abuse Alcoholism, Division of Intramural Clinical and Biological Research, TR 112, PO Box 529, Poolesville, MD 20837, USA. cbarr@mail.nih.gov

CONTEXT: Both highly stress-reactive and novelty-seeking individuals are susceptible to alcohol use disorders.

Variation in stress reactivity, exploration, and response to novelty have been attributed to differences in

corticotropin-releasing hormone (CRH) system function.

RESULTS: We show that 2232C>G alters DNA x protein interactions and confers decreased sensitivity of the CRH promoter to glucocorticoids in vitro. Consistent with the known effects of glucocorticoids on CRH expression in the brain,

carriers of the G allele had lower CSF levels of CRH but higher levels of ACTH.

Infants carrying the G allele were more exploratory and bold, and among adolescent and adult male macaques, the G allele was associated with exploratory/bold responding to an unfamiliar male. [sounds similar to vasopressin affects] Adults with the C/G genotype also exhibited increased alcohol consumption in the social group, a model for high-risk alcohol-seeking behavior. [Even in monkeys!]

CONCLUSION: Haplotypes that differ in terms of corticosteroid sensitivity have been identified in humans. Our data may suggest that functionally similar CRH variants could influence risk for externalizing disorders in human subjects.


Zuo et al 2007

Biol Psychiatry. 2007 Sep 15;62(6):616-26. Epub 2007 May 23.


CNR1 variation modulates risk for drug and alcohol dependence.

Zuo L, Kranzler HR, Luo X, Covault J, Gelernter J.

Department of Psychiatry, Yale University School of Medicine, 950 Campbell Avenue, New Haven, CT 06516, USA.

BACKGROUND: Human cannabinoid receptor 1 (CB1), which is encoded by the CNR1 gene, may play a role in the development of substance dependence (SD). Following initial reports of association of CNR1 with SD, we studied multiple markers at this locus in a large case-control sample. METHODS: Ten CNR1 markers and 38 ancestry-informative markers were genotyped in 451 healthy control subjects and 550 SD (AD and/or DD) patients (including European Americans [EAs] and African Americans [AAs]). Common confounding effects on association analysis of population stratification and admixture, age, and sex were controlled for using regression analysis. Disease risk and protective alleles were fine-mapped using a linkage disequilibrium measure (delta). RESULTS: In EAs, risk for each SD subtype significantly increased with the number of “G” alleles at rs6454674 (single nucleotide polymorphisms [SNP]3).

…. CONCLUSIONS: We demonstrate that CNR1 variation and interactive effects play important roles in risk for both DD and AD.  [they don’t say what AD and DD mean]


Sim-Selley 2003

Crit Rev Neurobiol. 2003;15(2):91-119.


Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids.

Sim-Selley LJ.

Department of Pharmacology & Toxicology, Institute for Drug & Alcohol Studies, Virginia Commonwealth University Medical College of Virginia, Richmond, Virginia 23298, USA. ljsimsel@hsc.vcu.edu

Marijuana produces a number of characteristic behaviors in humans and animals, including memory impairment, antinociception, and locomotor and psychoactive effects. However, tolerance and dependence to cannabinoids develops after chronic use, as demonstrated both clinically and in animal models. The potential therapeutic benefits of certain cannabinoid-mediated effects, as well as the use of marijuana for its psychoactive properties, has raised interest in understanding the cellular adaptations produced by chronic administration of this class of drugs.

The primary active constituent of marijuana, delta9-tetrahydrohydrocannabinol (THC), binds to specific G-protein-coupled receptors. The central nervous system (CNS) effects of THC are mediated by CB1 receptors, which couple primarily to inhibitory G-proteins.

High levels of CB1 receptors are found in the

.. basal ganglia,


…cortex, and

…cerebellum, consistent with the profile of behavioral effects.

……….Studies over the past decade have determined that CB1 receptors undergo downregulation and desensitization following chronic administration of THC or synthetic cannabinoid agonists.

……In general, these adaptations are regionally widespread and of considerable magnitude, and are thought to contribute to tolerance to cannabinoid-mediated behavioral effects.

Adaptation at the effector level has been more difficult to characterize, although it appears that

…. alterations in cyclic adenosine monophosphate (cAMP)

…..and protein kinase A (PKA) activity may be particularly important in cannabinoid dependence.

A striking characteristic of CB 1 receptor adaptation is the region dependence of the magnitude and rate of development of downregulation and desensitization. These regional differences may provide interesting insights into the mechanisms of CB1 receptors receptor signaling in different brain regions. Moreover, region-specific adaptations in CB1 receptors following chronic cannabinoid administration may produce differential adaptations at the in vivo level.

See also:

Prolonged recovery rate of CB1 receptor adaptation after cessation of long-term cannabinoid administration.

Sim-Selley LJ, Schechter NS, Rorrer WK, Dalton GD, Hernandez J, Martin BR, Selley DE.

Mol Pharmacol. 2006 Sep;70(3):986-96. Epub 2006 Jun 7.

PMID: 16760363 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Long-term administration of Delta9-tetrahydrocannabinol desensitizes CB1-, adenosine A1-, and GABAB-mediated inhibition of adenylyl cyclase in mouse cerebellum.

Selley DE, Cassidy MP, Martin BR, Sim-Selley LJ.

Mol Pharmacol. 2004 Nov;66(5):1275-84. Epub 2004 Jul 30.

PMID: 15286206 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Signaling pathways involved in the development of cannabinoid tolerance.

Martin BR, Sim-Selley LJ, Selley DE.

Trends Pharmacol Sci. 2004 Jun;25(6):325-30. Review.

PMID: 15165748 [PubMed – indexed for MEDLINE]

Related Articles

Effect of chronic administration of R-(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2) or delta(9)-tetrahydrocannabinol on cannabinoid receptor adaptation in mice.

Sim-Selley LJ, Martin BR.

J Pharmacol Exp Ther. 2002 Oct;303(1):36-44.

PMID: 12235230 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain.

Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Vogt LJ, Sim-Selley LJ.

J Neurochem. 1999 Dec;73(6):2447-59.

PMID: 10582605 [PubMed – indexed for MEDLINE]

Related Articles


Naidu et al 2007

Psychopharmacology (Berl). 2007 May;192(1):61-70. Epub 2007 Feb 6.


Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality.

Naidu PS, Varvel SA, Ahn K, Cravatt BF, Martin BR, Lichtman AH.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.

RATIONALE: Manipulations of the endocannabinoid/fatty acid amide hydrolase (FAAH) signaling systems

………..result in conflicting and paradoxical effects in rodent models

…….of emotional reactivity.

RESULTS: the …present results indicate that the pharmacological inhibition or genetic deletion of FAAH is ineffective in standard mouse models

of emotional reactivity.

……It remains to be established whether the effects of FAAH inhibition in these modified tasks are predictive of their efficacy in treating emotional disorders.


Domschke et al 2008b

Cannabinoid receptor 1 (CNR1) gene: impact on antidepressant treatment response and emotion processing in major depression.

Domschke K, Dannlowski U, Ohrmann P, Lawford B, Bauer J, Kugel H, Heindel W, Young R, Morris P, Arolt V, Deckert J, Suslow T, Baune BT.

Eur Neuropsychopharmacol. 2008 Oct;18(10):751-9. Epub 2008 Jun 24.

PMID: 18579347 [PubMed – indexed for MEDLINE]

Related Articles


The endocannabinoid system has been implicated in the

pathogenesis of depression and anxiety,

the mediation of antidepressant drug effects in animal models and the

neurobiology of emotion processing

in healthy volunteers.

Therefore, the impact of

cannabinoid receptor 1 gene (CNR1) variants

rs1049353 and


on antidepressant treatment response was evaluated in 256 Caucasian patients with Major Depression. A subsample of 33 depressed patients was additionally scanned by fMRI under visual presentation of emotional faces.

The CNR1 rs1049353 G allele conferred an increased risk of antidepressant treatment resistance, particularly in female patients with high comorbid anxiety.

CNR1 rs1049353 G allele carriers

also demonstrated weaker

bilateral amygdala,

putamen and

pallidum activity as well as

left lateralized caudate and


activity in response to masked happy faces.

This analysis provides preliminary support for a

role of CNR1 gene variation

in depression and anxiety,

potentially mediated by

subcortical hypo-responsiveness

to social reward stimuli.


See also:

Behav Pharmacol. 2007 Sep;18(5-6):431-8.


Local enhancement of cannabinoid CB1 receptor signalling in the dorsal hippocampus elicits an antidepressant-like effect.

McLaughlin RJ, Hill MN, Morrish AC, Gorzalka BB.

Department of Psychology, University of British Columbia, Vancouver, Canada.


Macri & Laviola 2004

Behav Brain Res. 2004 Sep 23;154(1):231-8.


Single episode of maternal deprivation and adult depressive profile in mice: interaction with cannabinoid exposure during adolescence.

Macrì S, Laviola G.

Department of Cell Biology and Neuroscience, Behavioural Neuroscience Section, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.

Early life adverse experiences have been shown to increase the likelihood of developing later depressive symptoms.

In this frame, human adolescents have been suggested to approach psychoactive drugs in order to self-medicate emerging depressive states.

In keeping with these considerations, outbred CD-1 mice of both sexes, which underwent a single 24-h episode of maternal deprivation early in development, were administered the cannabinoid agonist WIN 55,212-2 (0, 0.5 or 2 mg/kg i.p.) during adolescence.

Maternal deprivation

reduced the expected interest in socio-sexual interaction

with peers during adolescence.

Implications within the attachment matrix!

When mice were then tested at adulthood in the forced-swim paradigm in drug-free state, the latency to reach a passive floating posture was markedly reduced by early maternal deprivation. [they became passive sooner – ]

Low doses of cannabinoid (0.5 mg/kg) administered during adolescence were either able to reduce the time spent floating and to increase episodes of active struggling only in control non-deprived animals.

As a whole, the emergence of depressive symptoms during both adolescence and adulthood seems to be eased as a consequence of a single/prolonged episode of early maternal deprivation early in infancy.

Strange way of putting it – the early maternal deprivation makes it easier to become depressed – takes much less effort to become depressed!?!

Aso et al 2008

J Neurochem. 2008 Apr;105(2):565-72. Epub 2007 Nov 28.


BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice.

Aso E, Ozaita A, Valdizán EM, Ledent C, Pazos A, Maldonado R, Valverde O.

Grup de Recerca de Neurobiologia del Comportament (GRNC), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.


Stress can cause damage and atrophy of neurons

in the hippocampus

by deregulating

the expression of neurotrophic factors

that promote neuronal plasticity.

The endocannabinoid system represents a physiological substrate involved in neuroprotection at both cellular and emotional levels.

The lack of CB1 receptor alters neuronal plasticity and originates an anxiety-like phenotype in mice.

In the present study, CB1 knockout mice exhibited an augmented response to stress revealed by the increased despair behavior and corticosterone levels showed in the tail suspension test and decreased

brain derived neurotrophic factor (BDNF)

levels in the hippocampus.

Interestingly, local administration of BDNF in the hippocampus reversed the increased despair behavior of CB1 knockout mice, confirming the crucial role played by BDNF on the emotional impairment of these mutants. The neurotrophic deficiency seems to be specific for BDNF as no differences were found in the levels of nerve growth factor and NT-3, two additional neurotrophic factors.

Moreover, BDNF impairment is not related to the activity of its specific tyrosine kinase receptor or the activity of the transcription factor cAMP responsive element binding. These results suggest that the lack of CB1 receptor originates an enhanced response to stress and deficiency in neuronal plasticity by decreasing BDNF levels in the hippocampus that lead to impairment in the responses to emotional disturbances.


See also on complicated grief:

J Affect Disord. 2009 Mar 4. [Epub ahead of print]


Complicated grief in patients with unipolar depression.

Kersting A, Kroker K, Horstmann J, Ohrmann P, Baune BT, Arolt V, Suslow T.

Department of Psychiatry, University of Muenster, Germany.

J Clin Psychiatry. 2006 Feb;67(2):233-9.


Indirect self-destructive behavior and overt suicidality in patients with complicated grief.

Szanto K, Shear MK, Houck PR, Reynolds CF 3rd, Frank E, Caroff K, Silowash R.


Steiner et al 2008b

Psychoneuroendocrinology. 2008 Jan;33(1):54-67. Epub 2007 Oct 31.


Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exaggerated corticosterone secretion in mice.

Steiner MA, Marsicano G, Nestler EJ, Holsboer F, Lutz B, Wotjak CT.

Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. steinmi@uni-mainz.de

Hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity is associated with major depressive disorders,

and treatment with classical antidepressants ameliorates not only psychopathological symptoms, but also the dysregulation of the HPA axis.

Here, we further elucidated the role of impaired cannabinoid type 1 receptor (CB1) signaling for neuroendocrine and behavioral stress coping in the mouse forced swim test (FST). We demonstrate that the

genetic inactivation of CB1 is accompanied by increased plasma corticosterone levels both under basal conditions and at different time points following exposure to the FST. The latter effect could be mimicked in C57BL/6N mice by acute, subchronic, and chronic administration of the selective CB1 antagonist SR141716. Further experiments confirmed the specificity of corticosterone-elevating SR141716 actions for CB1 in CB1-deficient mice. Subchronic and chronic pharmacological blockade of CB1, but not its genetic deletion, induced antidepressant-like behavioral responses in the FST that were characterized by decreased floating and/or increased struggling behavior. The antidepressant-like behavioral effects of acute desipramine treatment in the FST were absent in CB1-deficient mice, but the dampening effects of desipramine on FST stress-induced corticosterone secretion were not compromised by CB1 deficiency. However, antidepressant-like behavioral desipramine effects were intact in C57BL/6N mice pre-treated with SR141716, indicating potential developmental deficits in CB1-deficient mice. We conclude that pharmacological blockade of CB1 signaling shares antidepressant-like behavioral effects with desipramine, but reveals opposite effects on HPA axis activity. Meaning what, exactly?


D’Souza et al 2008

Psychopharmacology (Berl). 2009 Mar;202(4):569-78. Epub 2008 Sep 21.


Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans.

D’Souza DC, Pittman B, Perry E, Simen A.

Schizophrenia Biological Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USA. deepak.dsouza@yale.edu

Acute and chronic exposure to cannabinoids has been associated with cognitive deficits, a higher risk for schizophrenia and other drug abuse. However, the precise mechanism underlying such effects is not known.

Preclinical studies suggest that


modulate brain-derived neurotrophic factor (BDNF).

Accordingly, we hypothesized that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the principal active component of cannabis, would alter BDNF levels in humans. MATERIALS AND METHODS: Healthy control subjects (n = 14) and light users of cannabis (n = 9) received intravenous administration of (0.0286 mg/kg) Delta(9)-THC in a double-blind, fixed order, placebo-controlled, laboratory study. Serum sampled at baseline, after placebo administration, and after Delta(9)-THC administration was assayed for BDNF using ELISA. RESULTS:

Delta(9)-THC increased serum BDNF levels in healthy controls but not light users of cannabis. Further, light users of cannabis had lower basal BDNF levels.

Delta(9)-THC produced psychotomimetic effects, perceptual alterations, and “high” and spatial memory impairments. IMPLICATIONS: The effects of socially relevant doses of cannabinoids on BDNF suggest a possible mechanism underlying the consequences of exposure to cannabis. This may be of particular importance for the developing brain and also in disorders believed to involve altered neurodevelopment such as schizophrenia. Larger studies to investigate the effects of cannabinoids on BDNF and other neurotrophins are warranted.

Linda note:  This study does not assess specific brain regions – does it affect the higher cortical development ongoing until way past adolescence?




Pezawas et al 2008

Mol Psychiatry. 2008 Jul;13(7):709-16. Epub 2008 Mar 18.


Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression.

Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR.

Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.

Complex genetic disorders such as depression likely exhibit epistasis [The masking of the effects of one gene by the action of another, example: widow’s peak masked by the baldness gene], but neural mechanisms of such gene-gene interactions are incompletely understood. 5-HTTLPR and BDNF VAL66MET, functional polymorphisms of the serotonin (5-HT) transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) gene,

impact on two distinct, but interacting signaling systems, which have been related to depression and to the modulation of neurogenesis and plasticity of circuitries of emotion processing.

Recent clinical studies suggest that the BDNF MET allele, which shows abnormal intracellular trafficking and regulated secretion, has a protective effect regarding the development of depression and in mice of social defeat stress.

Here we show, using anatomical neuroimaging techniques in a sample of healthy subjects (n=111), that the BDNF MET allele, which is predicted to have reduced responsivity to 5-HT signaling, protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate (rAC). Our analyses revealed no effect of the 5-HTTLPR S allele on rAC volume in the presence of BDNF MET alleles, whereas a significant volume reduction (P<0.001) was seen on BDNF VAL/VAL background. Interacting genotype effects were also found in structural connectivity between amygdala and rAC (P=0.002). These data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying

a neural mechanism linking serotonergic and neurotrophic signaling

on the neural systems level,

and have implications for personalized treatment planning in depression.


Hariri et al 2003

J Neurosci. 2003 Jul 30;23(17):6690-4.


Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance.

Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR.

Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland 20892-1384, USA.

BDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus.

A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val66met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the

met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects,

but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val66met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes.

Remarkably, the interaction between the BDNF val66met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance.

These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.


Hashimoto et al 2008

Neurosci Res. 2008 Aug;61(4):360-7. Epub 2008 Apr 20.


Dose-dependent effect of the Val66Met polymorphism of the brain-derived neurotrophic factor gene on memory-related hippocampal activity.

Hashimoto R, Moriguchi Y, Yamashita F, Mori T, Nemoto K, Okada T, Hori H, Noguchi H, Kunugi H, Ohnishi T.

The Osaka-Hamamatsu Joint Research Center For Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. hashimor@psy.med.osaka-u.ac.jp

Brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus.

Recent human studies have indicated that a common single nucleotide polymorphism of the BDNF gene, the Val66Met polymorphism, has impact on episodic memory, hippocampal morphology and memory-related hippocampal activity measured by functional magnetic resonance imaging (fMRI). However, two issues remain to be clarified: (1) whether the genotype effect of this polymorphism on memory-related brain activity is allele dose dependent and (2) whether the effect of this polymorphism in Asian population is the same as effects observed in Caucasian sample. To clarify these issues, we studied the relationship of the Val66Met polymorphism genotype and hippocampal activity during episodic memory task using fMRI in healthy 58 biologically unrelated Japanese. Although there was no genotype effect on episodic memory function obtained by behavioral assessments, fMRI measurements revealed a significantly negative correlation between the dose of Met-BDNF allele and encoding related brain activity in the bilateral hippocampi and right parahippocampal gyrus. There was no genotype effect on retrieval related brain activity.

These data indicated a genetic mechanism for normal variation in human memory and suggest effects of BDNF signaling on hippocampal function in humans.


See also:

J Neurosci. 2006 Jun 14;26(24):6643-50.


Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release.

Malcher-Lopes R, Di S, Marcheselli VS, Weng FJ, Stuart CT, Bazan NG, Tasker JG.

Neuroscience Program, Tulane University, New Orleans, Louisiana 70118, USA. malcherlopes@gmail.com


Bachmann et al 2005

Abstract – Department of Medicine, University of Queensland, Greenslopes Private Hospital, Brisbane, Qld 4120, Australia.

Post-traumatic stress disorder (PTSD) is reported in some studies to be associated with increased glucocorticoid (GC) sensitivity.

Two common glucocorticoid receptor (GR) polymorphisms (N363S and BclI) appear to contribute to the population variance in GC sensitivity.

There is some evidence that there may be a genetic predisposition to PTSD.

Hence we studied 118 Vietnam war veterans with PTSD for

(i) GR polymorphisms, particularly the N363S and the BclI polymorphisms which are thought to be GC sensitizing, and

(ii) two measures of GC sensitivity, the low-dose 0.25 mg dexamethasone suppression test (LD-DST) and the dermal vasoconstrictor assay (DVVA). The DST and GR polymorphisms were also performed in 42 combat exposed Vietnam war veterans without PTSD. Basal plasma cortisol levels were not significantly different in PTSD (399.5+/-19.2 nmol/L, N=75) and controls (348.6+/-23.0 nmol/L, N=33) and the LD-DST resulted in similar cortisol suppression in both groups (45.6+/-3.2 vs. 40.8+/-4.1%). The cortisol suppression in PTSD patients does not correlate with Clinician Administered PTSD Scores (CAPS), however there was a significant association between the BclI GG genotype and low basal cortisol levels in PTSD (P=0.048). The response to the DVVA was similar to controls … PTSD patients with the GG genotype, however, tended to be more responsive to DVVA and in this group the DVVA correlated with higher CAPS scores. The only exon 2 GR polymorphisms detected were the R23K and N363S.

……Heterozygosity for the N363S variant in PTSD, at 5.1% was not more prevalent than in other population studies of the N363S polymorphism in Caucasians (6.0-14.8%). The GG genotype of the BclI polymorphism found to be associated with increased GC sensitivity in many studies showed a tendency towards increased response with DVVA and correlated with higher CAPS scores.

In conclusion, the N363S and BclI GR polymorphisms were not more frequent in PTSD patients than controls and reported population frequencies. Our PTSD group did not display GC hypersensitivity, as measured by the LD-DST and DVVA. In a subset of PTSD patients with the BclI GG genotype, CAPS scores and basal cortisol levels were negatively correlated.


van Rossum et al 2004

Recent Prog Horm Res. 2004;59:333-57.


Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition.

van Rossum EF, Lamberts SW.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Most actions of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). The interindividual response to GCs varies considerably, as demonstrated by a variable suppressive response to 0.25-mg dexamethasone (DEX). Several polymorphisms in the gene coding for the GR have been described. It is unclear to what extent the observed response variability is due to GR polymorphisms or to other factors. However, at least three polymorphisms seem to be associated with altered GC sensitivity and changes in body composition and metabolic parameters.

….The N363S polymorphism has been associated with increased sensitivity to GCs, increased insulin response to DEX, a tendency towards lower bone mineral density, and increased body mass index (BMI). However, other reports found no associations with BMI.

…..Another polymorphism, previously described as a BclI restriction fragment length polymorphism, recently was identified as a C –> G nucleotide change. The G allele also was associated with increased sensitivity to GCs. In middle-aged subjects, the G allele of this BclI polymorphism was associated with increased abdominal obesity, while at older age, a lower BMI was found, accompanied by a tendency towards lower lean body mass.

…..A third polymorphism consists of two linked, single-nucleotide mutations in codons 22 and 23, of which the second mutation results in an amino acid change from arginine (R) to lysine (K). In contrast to the other polymorphisms, this ER22/23EK polymorphism was associated with a relative resistance to GCs.

This sensitivity and resistance is seen in depression…….in line with this, ER22/23EK carriers had lower total cholesterol and low-density lipoprotein cholesterol levels as well as lower fasting insulin concentrations and a better insulin sensitivity. C-reactive protein levels were lower in ER22/23EK carriers, as was found in a different population of elderly males.

………. In accordance with this healthy metabolic profile, we found in this population a significantly better survival in ER22/23EK carriers after a 4-year follow-up.

GCs also affect the brain. Although a certain level of


is essential for proper brain functioning, excessive GC levels have been shown to negatively affect brain morphology and functions. At older age, we found that the risk of dementia and white matter lesions was lower in ER22/23EK carriers.

……GCs are also important in the regulation of body fat distribution. At young age, we observed sex-specific differences in body composition. Male ER22/23EK carriers were taller, had more muscle mass, and were stronger than noncarriers. In young females, ER22/23EK carriers had tendencies towards smaller waist and hip circumferences and lower body weight.

……….Another polymorphism (TthIIII) was not associated with altered GC sensitivity. In conclusion, these

polymorphisms in the GR gene may contribute considerably to the observed variability in GC sensitivity.

As a result, they are associated with several differences in body composition and metabolic factors.  I also suspect these differences have to affect how the reflective endocannabinoid system operates, as well

See also:

Glucocorticoid receptor gene variant is associated with increased body fatness in youngsters.

Voorhoeve PG, van den Akker EL, van Rossum EF, Koper JW, van Mechelen W, Lamberts SW, Delemarre-van de Waal HA.

Clin Endocrinol (Oxf). 2009 Feb 16. [Epub ahead of print]

PMID: 19222494 [PubMed – as supplied by publisher]

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Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder.

Spijker AT, van Rossum EF, Hoencamp E, DeRijk RH, Haffmans J, Blom M, Manenschijn L, Koper JW, Lamberts SW, Zitman FG.

Bipolar Disord. 2009 Feb;11(1):95-101.

PMID: 19133972 [PubMed – indexed for MEDLINE]

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Two common haplotypes of the glucocorticoid receptor gene are associated with increased susceptibility to cardiovascular disease in men with familial hypercholesterolemia.

Koeijvoets KC, van der Net JB, van Rossum EF, Steyerberg EW, Defesche JC, Kastelein JJ, Lamberts SW, Sijbrands EJ.

J Clin Endocrinol Metab. 2008 Dec;93(12):4902-8. Epub 2008 Sep 23.

PMID: 18812484 [PubMed – indexed for MEDLINE]

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Prediction of treatment response by HPA-axis and glucocorticoid receptor polymorphisms in major depression.

Brouwer JP, Appelhof BC, van Rossum EF, Koper JW, Fliers E, Huyser J, Schene AH, Tijssen JG, Van Dyck R, Lamberts SW, Wiersinga WM, Hoogendijk WJ.

Psychoneuroendocrinology. 2006 Nov;31(10):1154-63. Epub 2006 Oct 10.

PMID: 17034955 [PubMed – indexed for MEDLINE]

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Staphylococcus aureus nasal carriage is associated with glucocorticoid receptor gene polymorphisms.

van den Akker EL, Nouwen JL, Melles DC, van Rossum EF, Koper JW, Uitterlinden AG, Hofman A, Verbrugh HA, Pols HA, Lamberts SW, van Belkum A.

J Infect Dis. 2006 Sep 15;194(6):814-8. Epub 2006 Aug 8.

PMID: 16941349 [PubMed – indexed for MEDLINE]

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Glucocorticoid receptor polymorphism affects transrepression but not transactivation.

van den Akker EL, Russcher H, van Rossum EF, Brinkmann AO, de Jong FH, Hokken A, Pols HA, Koper JW, Lamberts SW.

J Clin Endocrinol Metab. 2006 Jul;91(7):2800-3. Epub 2006 May 9.

PMID: 16684836 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

Polymorphisms of the glucocorticoid receptor gene and major depression.

van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S, Salyakina D, Lamberts SW, Holsboer F.

Biol Psychiatry. 2006 Apr 15;59(8):681-8.

PMID: 16580345 [PubMed – indexed for MEDLINE]

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Genetic polymorphisms and multifactorial diseases: facts and fallacies revealed by the glucocorticoid receptor gene.

van Rossum EF, Russcher H, Lamberts SW.

Trends Endocrinol Metab. 2005 Dec;16(10):445-50. Epub 2005 Nov 4. Review.

PMID: 16275120 [PubMed – indexed for MEDLINE]

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Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression.

Russcher H, Smit P, van den Akker EL, van Rossum EF, Brinkmann AO, de Jong FH, Lamberts SW, Koper JW.

J Clin Endocrinol Metab. 2005 Oct;90(10):5804-10. Epub 2005 Jul 19.

PMID: 16030164 [PubMed – indexed for MEDLINE]

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Increased expression of the glucocorticoid receptor-A translational isoform as a result of the ER22/23EK polymorphism.

Russcher H, van Rossum EF, de Jong FH, Brinkmann AO, Lamberts SW, Koper JW.

Mol Endocrinol. 2005 Jul;19(7):1687-96. Epub 2005 Mar 3.

PMID: 15746190 [PubMed – indexed for MEDLINE]

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Characterization of a promoter polymorphism in the glucocorticoid receptor gene and its relationship to three other polymorphisms.

van Rossum EF, Roks PH, de Jong FH, Brinkmann AO, Pols HA, Koper JW, Lamberts SW.

Clin Endocrinol (Oxf). 2004 Nov;61(5):573-81.

PMID: 15521959 [PubMed – indexed for MEDLINE]

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The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients.

Di Blasio AM, van Rossum EF, Maestrini S, Berselli ME, Tagliaferri M, Podestà F, Koper JW, Liuzzi A, Lamberts SW.

Clin Endocrinol (Oxf). 2003 Jul;59(1):68-74.

PMID: 12807506 [PubMed – indexed for MEDLINE]

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van Rossum et al 2006

Biol Psychiatry. 2006 Apr 15;59(8):681-8.


Polymorphisms of the glucocorticoid receptor gene and major depression.

van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S, Salyakina D, Lamberts SW, Holsboer F.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. e.vanrossum@erasmusmc.nl.

The most consistent biological finding

in patients with depression

is a hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis,

which might be caused by impaired glucocorticoid signaling.

Glucocorticoids act through the glucocorticoid receptor (GR) for which several polymorphisms have been described. The

N363S and BclI polymorphisms have been associated with hypersensitivity to glucocorticoids,

whereas the ER22/23EK polymorphism is related to glucocorticoid resistance.

METHODS: We studied whether the susceptibility to develop a depression is related to these polymorphisms by comparing depressive inpatients (n = 490) and healthy control subjects (n = 496). Among depressed patients, we also investigated the relation between GR variants and dysregulation of the HPA-axis, as measured by the combined dexamethasone suppression/corticotropin-releasing hormone (CRH)-stimulation test, clinical response to antidepressive treatment, and cognitive functioning. RESULTS:

Homozygous carriers of the BclI polymorphism and ER22/23EK-carriers had an increased risk of developing a major depressive episode.

We found no genetic associations with functional HPA-axis measures in depressed patients. The ER22/23EK-carriers, however, showed a significantly faster clinical response to antidepressant therapy as well as a trend toward better cognitive functioning during depression. CONCLUSIONS: The BclI and ER22/23EK polymorphisms were associated with susceptibility to develop major depression. In addition, the ER22/23EK polymorphism is associated with a faster clinical response to antidepressant treatment. These findings support the notion that variants of the GR gene might play a role in the pathophysiology of a major depression and can contribute to the variability of antidepressant response.


Brouwer et al 2006

Psychoneuroendocrinology. 2006 Nov;31(10):1154-63. Epub 2006 Oct 10.


Prediction of treatment response by HPA-axis and glucocorticoid receptor polymorphisms in major depression.

Brouwer JP, Appelhof BC, van Rossum EF, Koper JW, Fliers E, Huyser J, Schene AH, Tijssen JG, Van Dyck R, Lamberts SW, Wiersinga WM, Hoogendijk WJ.

Department of Endocrinology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. jantien.brouwer@gmail.com

OBJECTIVE: We investigated whether treatment response is predicted by hypothalamus-pituitary-adrenal (HPA) axis parameters, or by genetic polymorphisms in the glucocorticoid receptor (GR), that regulates its feedback. METHODS: Ninety-eight outpatients completed 8 weeks of paroxetine treatment. Treatment response was defined as a 50% decrease in Hamilton Rating Scale for depression (HRSD) ratings. At baseline, 24h urinary cortisol excretion, and cortisol and ACTH concentrations in a DEX/CRH test were measured. The presence of polymorphisms in the GR DNA sequence (BclI, ER22/23EK, N363S) was determined. Prediction of treatment response was analyzed by calculating response rates per tertile of an HPA-axis parameter and per GR genotype. RESULTS: The response rate in the high ACTH tertile was significantly lower as compared to the intermediate tertile, but not compared to the low tertile (response rates from high to low tertile: 33%, 67% and 42%). Carriers of the BclI polymorphism had higher ACTH values than non-carriers (baseline ACTH: 3 versus 5ng/l, p=0.02) and showed a trend towards lower decrease of HRSD rates than non-carriers (HRSD decrease: 8 versus 11, respectively, p=0.07). In a subgroup of BclI carriers, patients in the high ACTH tertile had a lower decrease in HRSD and lower response rates than patients in the low ACTH tertiles (HRSD decrease from high to low tertile: 5, 9 and 11, p<0.01). CONCLUSION: The results suggest that hyperactivity of the HPA-axis predict worse treatment outcome. The BclI polymorphism explains, in part, DEX/CRH test results and tends to be associated with worse treatment outcome.



Bortolato et al 2007

Biol Psychiatry. 2007 Nov 15;62(10):1103-10. Epub 2007 May 23.


Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress.

Bortolato M, Mangieri RA, Fu J, Kim JH, Arguello O, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D.

Department of Pharmacology, University of California, Irvine, California 92697-4260, USA

BACKGROUND: The endocannabinoid anandamide may be involved in the regulation of emotional reactivity.

In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH),

….which catalyzes the intracellular hydrolysis of anandamide,

….elicits anxiolytic-like and antidepressant-like effects in rodents.

METHODS: We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression.

RESULTS: Daily administration of URB597 (.3 mg kg(-1), intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg kg(-1), once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg kg(-1)) or ineffective (.03 mg kg(-1)). Treatment with URB597 (.3 mg kg(-1)) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore,

the drug regimen increased anandamide levels in midbrain, striatum, and thalamus.

CONCLUSIONS: URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression.

…….These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.


See also:

Search “Glucocorticoids cannabinoid” in the pubmed database for 54 articles related to depression, anxiety and HPA function


Hill et al 2007

Electroconvulsive shock treatment differentially modulates cortical and subcortical endocannabinoid activity.

Hill MN, Barr AM, Ho WS, Carrier EJ, Gorzalka BB, Hillard CJ.

J Neurochem. 2007 Oct;103(1):47-56. Epub 2007 Jun 11.

PMID: 17561935 [PubMed – indexed for MEDLINE]

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Previous studies indicate that the endocannabinoid system is a potential target for the treatment of depression. To further examine this question we assessed the effects of electroconvulsive shock (ECS) treatment, both a single session and 10 daily sessions, on endocannabinoid content, CB(1) receptor binding parameters and CB(1) receptor-mediated [(35)S]GTPgammaS binding in the prefrontal cortex, hippocampus, hypothalamus and amygdala.

A single ECS session resulted in a general reduction in the binding affinity of the CB(1) receptor in all brain regions examined, as well as reductions in N-arachidonylethanolamine (anandamide) content in the prefrontal cortex and the hippocampus, reduced hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) in the prefrontal cortex and an increase in the binding site density of the CB(1) receptor in the amygdala.

Following 10 ECS sessions, all these effects subsided except for the reductions in anandamide content in the prefrontal cortex, which increased in magnitude, as well as the reductions in FAAH activity in the prefrontal cortex.

Additionally, repeated ECS treatment resulted in a significant reduction in the binding site density of the CB(1) receptor in the prefrontal cortex, but did not alter CB(1) receptor-mediated [(35)S]GTPgammaS binding.

……Repeated ECS treatment also significantly enhanced the sensitivity of CB(1) receptor-mediated [(35)S]GTPgammaS binding in the amygdala.

Collectively, these data demonstrate that ECS

treatment results in a down-regulation of cortical

and an up-regulation of subcortical endocannabinoid activity,

illustrating the possibility that the role of the endocannabinoid system

in affective illness may be both

complex and regionally specific.


Onaivi et al 2008

Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects.

Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Perchuk A, Mora Z, Tagliaferro PA, Gardner E, Brusco A, Akinshola BE, Hope B, Lujilde J, Inada T, Iwasaki S, Macharia D, Teasenfitz L, Arinami T, Uhl GR.

PLoS One. 2008 Feb 20;3(2):e1640.

PMID: 18286196 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

BACKGROUND: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment.

Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs) in healthy brains,

………..but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation.

Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown.

METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents.

……. Here we demonstrate that a high incidence of (Q63R) but not (H316Y) polymorphism in the CB2 gene

…….was found in Japanese depressed subjects.

CB2-Rs and their gene transcripts

are expressed in the brains of naïve mice

and are modulated following exposure

to stressors

and administration of abused drugs.

Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the

functional presence of CB2-Rs in the brain

that modifies behavior.

We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders

beyond neuro-immunocannabinoid activity.


See also:

Functional expression of brain neuronal CB2 cannabinoid receptors are involved in the effects of drugs of abuse and in depression.

Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Perchuk A, Mora Z, Tagliaferro PA, Gardner E, Brusco A, Akinshola BE, Liu QR, Chirwa SS, Hope B, Lujilde J, Inada T, Iwasaki S, Macharia D, Teasenfitz L, Arinami T, Uhl GR.

Ann N Y Acad Sci. 2008 Oct;1139:434-49.

PMID: 18991891 [PubMed – indexed for MEDLINE]

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Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans.

Ishiguro H, Iwasaki S, Teasenfitz L, Higuchi S, Horiuchi Y, Saito T, Arinami T, Onaivi ES.

Pharmacogenomics J. 2007 Dec;7(6):380-5. Epub 2006 Dec 26.

PMID: 17189959 [PubMed – indexed for MEDLINE]

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Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse.

Zhang PW, Ishiguro H, Ohtsuki T, Hess J, Carillo F, Walther D, Onaivi ES, Arinami T, Uhl GR.

Mol Psychiatry. 2004 Oct;9(10):916-31.

PMID: 15289816 [PubMed – indexed for MEDLINE]

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Psychopharmacology (Berl). 2005 Dec;183(3):368-77. Epub 2005 Oct 15.


Involvement of the endogenous cannabinoid system in the effects of alcohol in the mesolimbic reward circuit: electrophysiological evidence in vivo.

Perra S, Pillolla G, Melis M, Muntoni AL, Gessa GL, Pistis M.

B.B. Brodie Department of Neuroscience, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, CA, Italy


Tyndale et al 2007

Am J Med Genet B Neuropsychiatr Genet. 2007 Jul 5;144B(5):660-6.


The fatty acid amide hydrolase C385A (P129T) missense variant in cannabis users: studies of drug use and dependence in Caucasians.

Tyndale RF, Payne JI, Gerber AL, Sipe JC.

Department of Pharmacology, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada.

A genetic variation in fatty acid amide hydrolase (FAAH), C385A (P129T), has been previously associated with risk for problem street drug use. FAAH is a mammalian enzyme that inactivates neuromodulatory-signaling lipids including the endogenous cannabinoid 1 receptor agonist anandamide. We investigated in adult Caucasians (N = 749) whether this FAAH variant altered the risk for trying, regular use of or dependence on cannabis, alcohol or nicotine, traditional “gateway” drugs. Consistent with our knowledge that the A/A genotype results in reduced FAAH expression and activity in humans, subjects with the A/A genotype were less likely to be THC dependent than subjects with either a C/C or C/A genotype (11% vs. 26%, P < 0.05). No association was observed between the A/A genotype and risk for alcohol or tobacco regular use, or DSM IV dependence. Controlling for regular use of nicotine and sedatives, both identified as confounders, those with the A/A genotype were at significantly reduced risk for being THC dependent (OR 0.25, 95% CI: 0.07-0.88) as compared with those with the C/A or C/C genotype, supporting a link between alterations in the endocannabinoid system and THC dependence.

Unexpectedly, we found an increased risk for regular use of sedatives among the A/A genotype group. The relationship between the FAAH A/A genotype and risk for drug dependence in this study was drug class specific, suggesting it is not part of a more general drug abuse effect. These results, particularly the observation of altered risk for sedative drug use, should be investigated further in multiple ethnic populations.


Xiao et al 2008

Similar in vitro pharmacology of human cannabinoid CB1 receptor variants expressed in CHO cells.

Xiao JC, Jewell JP, Lin LS, Hagmann WK, Fong TM, Shen CP.

Brain Res. 2008 Oct 31;1238:36-43. Epub 2008 Aug 18.

PMID: 18761332 [PubMed – indexed for MEDLINE]

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Through alternative splicing, the human cannabinoid CB(1) receptor gene encodes three variants of protein products (hCB(1), hCB(1a), and hCB(1b)) that differ in amino acid sequence at the N terminus of the receptors.

By semi-quantitative PCR from human adult and fetal brain mRNA, we demonstrated that the transcript encoding hCB(1) is the major transcript, and estimated that those of hCB(1a) and hCB(1b) represent fewer than 5% of the total human cannabinoid CB(1) receptor transcripts.

We characterized the three variants stably expressed in CHO cells.  In the contrary to the study by Ryberg et al. (FEBS Lett 579[1], 259-64), we did not find substantial difference among the three variants according to the binding affinity, functional potency, and efficacy of meth-anandamide, 2-arachidonoyl glycerol, virodhamine, Noladin ether, docosatetraenylethanolamide, CP55940, AM251, and compound 35e (an acyclic class human CB(1) receptor inverse agonist similar to MK-0364).

The functional significance of different human cannabinoid CB(1) receptor variants remains to be clarified.


See also:

Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor.

Chen RZ, Frassetto A, Lao JZ, Huang RR, Xiao JC, Clements MJ, Walsh TF, Hale JJ, Wang J, Tong X, Fong TM.

Eur J Pharmacol. 2008 Apr 28;584(2-3):338-42. Epub 2008 Feb 19.

PMID: 18336811 [PubMed – indexed for MEDLINE]

Related Articles


Tham et al 2005

Abstract – Australia

[note – the mu receptors are involved with our attachment system]

1. Cannabinoid receptor agonists elicit analgesic effects in acute and chronic pain states via spinal and supraspinal pathways.

We investigated whether the combination of a cannabinoid agonist with other classes of antinociceptive drugs exerted supra-additive (synergistic) or additive effects in acute pain models in mice. 2. The interactions between the cannabinoid agonist CP55,940, alpha2-adrenoceptor agonist dexmedetomidine and mu-opioid receptor agonist morphine were evaluated by …. Drug interactions were examined … 3. CP55,940, dexmedetomidine and morphine all caused dose-dependent antinociception. … Synergistic interactions existed between CP55,940 and dexmedetomidine … and CP55,940 and morphine in both assays. Additive interactions were found for CP55,940 and dexmedetomidine … and dexmedetomidine and morphine in both assays. 4. Thus, an alpha2-adrenoceptor agonist or mu opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception …. However, for the tail flick nociceptive response to heat, only cannabinoid and mu opioid receptor antinociceptive synergy was demonstrated. If these results translate to humans, then prudent selection of dose and receptor-specific agonists may allow an improved therapeutic separation from unwanted side effects.


See also:

Expert Opin Investig Drugs. 2007 Jul;16(7):951-65.


Targeting cannabinoid agonists for inflammatory and neuropathic pain.

Cheng Y, Hitchcock SA.

Amgen, Inc., Chemistry Research and Development, MS 29-2-C, Thousand Oaks, CA 91320, USA. yuanc@amgen.com

Chem Phys Lipids. 2002 Dec 31;121(1-2):191-200.


Inhibition of pain responses by activation of CB(2) cannabinoid receptors.

Malan TP Jr, Ibrahim MM, Vanderah TW, Makriyannis A, Porreca F.

Department of Anesthesiology, The University of Arizona, PO Box 245114, Tucson, AZ 85724-5114, USA. malan@u.arizona.edu

Pain. 2001 Sep;93(3):239-45.


CB2 cannabinoid receptor-mediated peripheral antinociception.

Malan TP Jr, Ibrahim MM, Deng H, Liu Q, Mata HP, Vanderah T, Porreca F, Makriyannis A.

Department of Anesthesiology and Pharmacology, University of Arizona, Tucson, AZ 85724, USA. malan@u.arizona.edu

Prog Neurobiol. 2001 Apr;63(5):569-611.


Cannabinoid receptors and pain.

Pertwee RG.

Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Scotland, Aberdeen, UK. rgp@aberdeen.ac.uk

Curr Med Chem. 1999 Aug;6(8):635-64.


Pharmacology of cannabinoid receptor ligands.

Pertwee RG.

Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland.

Pharmacol Ther. 1997;74(2):129-80.


Pharmacology of cannabinoid CB1 and CB2 receptors.

Pertwee RG.

Department of Biomedical Sciences, Institute of Medical Sciences, Foresterhill, UK.


McCarberg 2007

J Pain Palliat Care Pharmacother. 2007;21(3):19-28.


Cannabinoids:their role in pain and palliation.

McCarberg BH.

Department of Family Medicine, Kaiser Permanente, 752 N Broadway, Escondido, CA 92025, USA. Bill.H.Mccarberg@kp.org

Controversy is associated with the issue of cannabis and cannabinoids in clinical care in the United States. Recent research has demonstrated the

underlying mechanisms of cannabinoid analgesia

via endocannabinoids, an endogenous system of

retrograde neuromodulatory messengers

that work in tandem with endogenous opioids.

Additional receptor and non-receptor mechanisms of cannabinoid drugs have pertinent activity, including anti-carcinogenesis and neuroprotection, that may be of key importance in aging and terminal patient populations. The results of clinical trials with synthetic and plant-based cannabinoids suggest that the role of formulation and delivery system is critical in optimizing the risk-benefit profile of cannabinoid products.

Synergy between opioids and cannabinoids may produce opioid-sparing effects, as well as extend the duration of analgesia and reduce opioid tolerance and dependence. This article reviews the mechanism of action of cannabinoids, examines marketed agents and those in clinical trials, and addresses their role in treatment of chronic pain, cancer, neurodegenerative diseases, and HIV/ AIDS. The ability of cannabinoid medicines to treat pain, associated sleep disorders, appetite loss, muscle spasm and a wide variety of other symptoms suggests that such agents may in the future play an important role in palliative care.


Lichtman et al 2004

Pain. 2004 Jun;109(3):319-27.


Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia.

Lichtman AH, Shelton CC, Advani T, Cravatt BF.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA. alichtma@hsc.vcu.edu

Although the N-arachidonoyl ethanolamine (anandamide) binds to cannabinoid receptors and has been implicated in the suppression of pain, its rapid catabolism in vivo by fatty acid amide hydrolase (FAAH) has presented a challenge in investigating the physiological functions of this endogenous cannabinoid.

In order to test whether anandamide and other non-cannabinoid fatty amides modulate nociception, we compared FAAH (+/+) and (-/-) mice in the tail immersion, hot plate, and formalin tests, as well as for thermal hyperalgesia in the carrageenan and the chronic constriction injury (CCI) models. FAAH (-/-) mice exhibited a CB1 receptor-mediated phenotypic hypoalgesia in thermal nociceptive tests.

These mice also exhibited CB1 receptor-mediated hypoalgesia in both phases of the formalin test accompanied with a phenotypic anti-edema effect, which was not blocked by either CB1 or CB2 antagonists. Additionally, FAAH (-/-) mice displayed thermal anti-hyperalgesic and anti-inflammatory effects in the carrageenan model that were mediated, in part, by CB2, but not CB1 receptors. In contrast, no genotype differences in pain behavior were evident following CCI [injury] , which was instead found to obliterate the phenotypic hypoalgesia displayed by FAAH (-/-) mice in the tail immersion and hot plate tests, suggesting that nerve injury may promote adaptive changes in these animals.

Collectively, these findings demonstrate a

cannabinoid receptor-mediated analgesic phenotype in FAAH (-/-) mice.

In more general terms, these findings suggest that selective inhibitors of FAAH might represent a viable pharmacological approach for the clinical treatment of pain disorders.

Take away the FAAH, take away the pain


Suplita et al 2006

Neuropharmacology. 2006 Mar;50(3):372-9. Epub 2005 Nov 28.


Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia.

Suplita RL 2nd, Gutierrez T, Fegley D, Piomelli D, Hohmann AG.

Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Baldwin Street, Athens, GA 30602-3013, USA.

Recent work in our laboratories has demonstrated that an

…..opioid-independent form of stress-induced analgesia (SIA) is mediated by endogenous cannabinoids [Hohmann et al., 2005. Nature 435, 1108].

Non-opioid SIA, induced by a 3-min continuous foot shock, is characterized by ….the mobilization of two endocannabinoid lipids–2-arachidonoylglycerol (2-AG) and anandamide—

…..in the midbrain periaqueductal gray (PAG).

The present studies were conducted to examine the

……contributions of spinal endocannabinoids to nonopioid SIA.

Time-dependent increases in levels of 2-AG, but not anandamide, were observed in lumbar spinal cord extracts derived from shocked relative to non-shocked rats.

Notably, 2-AG accumulation was of smaller magnitude than that observed previously in the dorsal midbrain following foot shock. 2-AG is preferentially degraded by monoacylglycerol lipase (MGL), whereas anandamide is hydrolyzed primarily by fatty-acid amide hydrolase (FAAH).

………… This metabolic segregation enabled us to manipulate endocannabinoid tone at the spinal level to further evaluate the roles of 2-AG and anandamide in nonopioid SIA.

Intrathecal administration of the competitive CB1 antagonist SR141716A (rimonabant) failed to suppress nonopioid SIA, suggesting that

…..supraspinal rather than spinal CB1 receptor activation

…….plays a pivotal role in endocannabinoid-mediated SIA.

By contrast, spinal inhibition of MGL using URB602,

….which selectively inhibits 2-AG hydrolysis in the PAG,

…..enhanced SIA through a CB1-selective mechanism.

Spinal inhibition of FAAH, with either URB597 or arachidonoyl serotonin (AA-5-HT),

….also enhanced SIA through a CB1-mediated mechanism,

….presumably by increasing accumulation of tonically released anandamide.

…….Our results suggest that endocannabinoids

…..in the spinal cord regulate,

……but do not mediate, nonopioid SIA.


Benamar, Geller & Adler 2008

J Pharmacol Exp Ther. 2008 May;325(2):641-5. Epub 2008 Feb 15.


Erratum in:

J Pharmacol Exp Ther. 2008 Jun;325(3):1061.

First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain.

Benamar K, Geller EB, Adler MW.

Center of Substance Abuse Research, Temple University School of Medicine, 3400 N. Broad St., Philadelphia, PA 19140, USA. kbenamar@temple.edu


in the fear section:

Martinez et al 2007b

Eur Neuropsychopharmacol. 2007 Nov;17(11):717-24. Epub 2007 Mar 29.


Serotonergic mechanisms in the basolateral amygdala differentially regulate the conditioned and unconditioned fear organized in the periaqueductal gray.

Martinez RC, Ribeiro de Oliveira A, Brandão ML.

Instituto de Neurociências & Comportamento-INeC, Campus USP, 14040-901, Ribeirão Preto, SP, Brazil


de Novellis et al 2005

Neuroscience. 2005;134(1):269-81.


Periaqueductal grey CB1 cannabinoid and metabotropic glutamate subtype 5 receptors modulate changes in rostral ventromedial medulla neuronal activities induced by subcutaneous formalin in the rat.

de Novellis V, Mariani L, Palazzo E, Vita D, Marabese I, Scafuro M, Rossi F, Maione S.

Department of Experimental Medicine, Section of Pharmacology “L. Donatelli,” Faculty of Medicine and Surgery, Second University of Naples, Via Costantinopoli 16, 80138 Napoli, Italy.

This study was undertaken to analyze the involvement of periaqueductal gray (PAG) cannabinoid or group I metabotropic glutamate receptors in the formalin-induced changes on the

rostral ventromedial medulla (RVM) ON- and OFF-cells activities…. the physiological stimulation of PAG mGlu5, but not mGlu1 glutamate receptors, seems to be required for the cannabinoid-mediated effect.


Cravatt & Lichtman 2004

J Neurobiol. 2004 Oct;61(1):149-60.


The endogenous cannabinoid system and its role in nociceptive behavior.

Cravatt BF, Lichtman AH.

The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, California 92037, USA. cravatt@scripps.edu

The analgesic properties of exogenous cannabinoids have been recognized for many years and suggest a regulatory role for the endogenous cannabinoid (“endocannabinoid”) system in mammalian nociceptive pathways.

The endocannabinoid system includes:

(1) at least two families of lipid signaling molecules, the N-acyl ethanolamines (e.g., anandamide) and the monoacylglycerols (e.g., 2-arachidonoyl glycerol);

(2) multiple enzymes involved in the biosynthesis and degradation of these lipids, including the integral membrane enzyme fatty acid amide hydrolase; and

(3) two G-protein coupled receptors, CB1 and CB2, which are primarily localized to the nervous system and immune system, respectively.

Here, we review recent genetic, behavioral, and pharmacological studies that have tested the function of the endocannabinoid system in pain sensation. Collectively, these investigations support a role for endocannabinoids in modulating behavioral responses to acute, inflammatory, and neuropathic pain stimuli.

See also:

Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain.

Kinsey SG, Long JZ, O’Neal ST, Abdullah RA, Poklis JL, Boger DL, Cravatt BF, Lichtman AH.

J Pharmacol Exp Ther. 2009 Jun 5. [Epub ahead of print]

PMID: 19502530 [PubMed – as supplied by publisher]

Related Articles Free article at journal site


Martin & Lichtman 1998

Neurobiol Dis. 1998 Dec;5(6 Pt B):447-61.


Cannabinoid transmission and pain perception.

Martin BR, Lichtman AH.

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond 23298, USA.

The use of cannabis for the management of a wide range of painful disorders has been well documented in case reports throughout history. However, clinical evaluations of cannabis and its psychoactive constituent THC have not led to a consensus regarding their analgesic effectiveness. On the other hand, THC and its synthetic derivatives have been shown to be effective in most animal models of pain. These antinociceptive effects are mediated through cannabinoid receptors in the brain that in turn appear to interact with noradrenergic and kappa opioid systems in the spinal cord to modulate the perception of painful stimuli.

The endogenous ligand, anandamide, is also an effective antinociceptive agent. The extent to which the endogenous cannabinoid system is involved in the modulation of pain is currently unknown.


Maione et al 2007

Br J Pharmacol. 2007 Mar;150(6):766-81. Epub 2007 Feb 5.


Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors.

Maione S, De Petrocellis L, de Novellis V, Moriello AS, Petrosino S, Palazzo E, Rossi FS, Woodward DF, Di Marzo V.

Department of Experimental Medicine, Section of Pharmacology L Donatelli, Second University of Naples, Naples, Italy.

BACKGROUND AND PURPOSE: N-arachidonoyl-serotonin (AA-5-HT) is an inhibitor of fatty acid amide hydrolase (FAAH)-catalyzed hydrolysis of the endocannabinoid/ endovanilloid compound, anandamide (AEA).

CONCLUSIONS AND IMPLICATIONS: Possibly due to its dual activity as a FAAH inhibitor and TRPV1 antagonist, AA-5-HT was highly effective against both

acute and chronic peripheral pain.


de Novellis et al 2008

Neuropharmacology. 2008 Dec;55(7):1105-13. Epub 2008 Jun 20.


The analgesic effect of N-arachidonoyl-serotonin, a FAAH inhibitor and TRPV1 receptor antagonist, associated with changes in rostral ventromedial medulla and locus coeruleus cell activity in rats.

de Novellis V, Palazzo E, Rossi F, De Petrocellis L, Petrosino S, Guida F, Luongo L, Migliozzi A, Cristino L, Marabese I, Starowicz K, Di Marzo V, Maione S; Endocannabinoid Research Group.

Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy.

We evaluated the effects of intra-periaqueductal grey (PAG)

N-arachidonoyl-serotonin (AA-5-HT),

a compound with a “dual” ability to inhibit the fatty acid amide hydrolase (FAAH) and to antagonize transient receptor vanilloid type 1 (TRPV1) receptors,

on endocannabinoid levels, rostral ventromedial medulla (RVM) ON and OFF cell activities, thermal nociception (tail flick in anaesthetized rats) and formalin-induced nocifensive responses in awake rats. AA-5-HT increased endocannabinoid levels in the PAG and induced analgesia.

Paradoxically, it also depressed the RVM OFF cell, as well as the ON cell activities. … thus suggesting that co-localization of these receptors in the PAG can be an appropriate neural substrate for AA-5-HT-induced analgesia.


Maione et al 2006

J Pharmacol Exp Ther. 2006 Mar;316(3):969-82. Epub 2005 Nov 11.


Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors.

Maione S, Bisogno T, de Novellis V, Palazzo E, Cristino L, Valenti M, Petrosino S, Guglielmotti V, Rossi F, Di Marzo V.

Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy.

In the ventrolateral periaqueductal gray (PAG),

….activation of excitatory output neurons projecting monosynaptically to OFF cells in the rostral ventromedial medulla (RVM)

…..causes antinociceptive responses and is under the control of cannabinoid receptor type-1 (CB1) and vanilloid transient receptor potential vanilloid type 1 (TRPV1) receptors. .


affect the descending pathways of pain control

by acting at either CB1 or TRPV1 receptors

in healthy rats.

See also:

Neuropharmacology. 2007 Feb;52(2):415-22. Epub 2006 Sep 29.


Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats.

Petrosino S, Palazzo E, de Novellis V, Bisogno T, Rossi F, Maione S, Di Marzo V.

Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (C.N.R.), Via Dei Campi Flegrei 34, Comprensorio Olivetti, Pozzuoli, Naples 80078, Italy.


Jhaveri, Richardson & Chapman 2007

Br J Pharmacol. 2007 Nov;152(5):624-32. Epub 2007 Aug 20.


Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain.

Jhaveri MD, Richardson D, Chapman V.

School of Biomedical Sciences, Institute of Neuroscience, Queens Medical Centre, Nottingham, UK. maulik.jhaveri@nottingham.ac.uk

Cannabinoid CB1 and CB2 receptors are located at key sites involved in the relaying and processing of noxious inputs.

Both CB1 and CB2 receptor agonists have analgesic effects in a range of models of inflammatory and neuropathic pain.

………Importantly, clinical trials of cannabis-based medicines indicate that the pre-clinical effects of cannabinoid agonists may translate into therapeutic potential in humans.

……….One of the areas of concern with this pharmacological approach is that CB1 receptors have a widespread distribution in the brain and that global activation of CB1 receptors is associated with adverse side effects.

Studies of the endogenous cannabinoids (endocannabinoids) have demonstrated that they are present in most tissues and that

…….in some pain states, such as neuropathic pain,

……levels of endocannabinoids are elevated at key sites involved in pain processing.

This is important in the “legalization debate.”  The endogenous system creates the substance ON DEMAND and LOCALIZED where needed!

An alternative approach that can be used to harness the potential therapeutic effects of cannabinoids is to maximise the effects of the endocannabinoids, the actions of which are terminated by re-uptake and metabolism by various enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and cyclooxygenase type 2 (COX2).

Preventing the metabolism, or uptake, of endocannabinoids elevates levels of these lipid compounds in tissue and produces behavioural analgesia in models of acute pain.

Self medicating with pot – a huge risk for those who are super sensitive in the first place, and then suffer trauma and abuse

Herein we review recent studies of the effects of inhibition of metabolism of endocannabinoids versus uptake of endocannabinoids on nociceptive processing in models of inflammatory and neuropathic pain.


Schoffelmeer et al 2006

Abstract – Department of Anatomy and Neurosciences, Institute for Clinical and Experimental Neurosciences, VU medical center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. anm.schoffelmeer@vumc.nl

We examined the occurrence of

functional interactions between CB1 cannabinoid and mu opioid receptors in the core of rat nucleus accumbens (NAc core).

To that end, receptor-mediated inhibition of depolarization (4-aminopyridine)-induced [3H]glutamate release and glutamate (NMDA) receptor-stimulated [14C]acetylcholine (ACh) and [3H]GABA release was studied in superfused NAc core slices. The inhibitory effects of the mu receptor agonist morphine and the CB1 receptor agonist HU210 on the release of these neurotransmitters were selectively antagonized by the mu receptor antagonist naloxone and the CB1 receptor antagonist SR141716A, respectively. Surprisingly, naloxone prevented the antagonistic action of SR141716A at CB1 receptors and SR141716A abolished that of naloxone at mu receptors mediating inhibition of [3H]glutamate and [3H]GABA release. Therefore, these antagonists seem to allosterically interact, indicating the involvement of physically associated mu opioid and CB1 cannabinoid receptors. Such an interaction between antagonists was not observed at the receptors mediating inhibition of [14C]ACh release. Moreover, dose-response curves of the agonists showed that mu and CB1 receptors mediating inhibition of [3H]glutamate release display a non-additive interaction, whereas these receptors synergistically interact regarding their inhibitory control of [3H]GABA release. Finally, the apparent allosteric interaction between antagonists was also observed regarding the effects of other receptor-selective agonists and antagonists at mu opioid and CB1 cannabinoid receptors (mediating inhibition of NMDA-induced [3H]GABA release) and must therefore be a unique property of the receptors involved.

These data suggest the existence of

physically associated mu opioid and CB1 cannabinoid receptors, whereby activation of these receptors results in

either a non-additive (glutamate release)

or a synergistic (GABA release) effect.

It is proposed that these allosterically interacting mu and CB1 receptors in the NAc core may represent G-protein coupled heterodimeric receptor complexes.


Sim-Selley et al 2002

Life Sci. 2002 Sep 27;71(19):2217-26.


Cellular localization of cannabinoid receptors and activated G-proteins in rat anterior cingulate cortex.

Sim-Selley LJ, Vogt LJ, Vogt BA, Childers SR.

Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Box 980524, Virginia Commonwealth University Medical College of Virginia, Richmond, VA 23298, USA. ljsimsel@hsc.vcu.edu

Cannabinoid receptors are found in moderate density throughout the cerebral cortex. The anterior cingulate cortex (ACC) [see attachment-pain] is of particular interest due its high level of cannabinoid receptors and role in behaviors known to be modulated by cannabinoids…These results indicate that cannabinoid receptors in laminae I and VI of the ACC are located on somatodendritic elements or axons intrinsic to the ACC. In addition, differences in the relative levels of cannabinoid binding sites and activated G-proteins between cortical laminae indicate that the efficiency of cannabinoid receptors for G-protein activation may vary within a specific brain region.

See also:

Distribution of ORL-1 receptor binding and receptor-activated G-proteins in rat forebrain and their experimental localization in anterior cingulate cortex.

Sim-Selley LJ, Vogt LJ, Childers SR, Vogt BA.

Neuropharmacology. 2003 Aug;45(2):220-30.

PMID: 12842128 [PubMed – indexed for MEDLINE]

Related Articles

Colocalization of mu-opioid receptors and activated G-proteins in rat cingulate cortex.

Vogt LJ, Sim-Selley LJ, Childers SR, Wiley RG, Vogt BA.

J Pharmacol Exp Ther. 2001 Dec;299(3):840-8.

PMID: 11714867 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site


Xing & Li 2007

Abstract – PA

J Neurophysiol. 2007 Jan;97(1):503-11. Epub 2006 Oct 25.


TRPV1 receptor mediates glutamatergic synaptic input to dorsolateral periaqueductal gray (dl-PAG) neurons.

Xing J, Li J.

The purpose of this study was to determine the role of transient receptor potential vanilloid type 1 (TRPV1) receptor

…..in modulating neuronal activity

of the dorsolateral periaqueductal gray (dl-PAG)

through excitatory and inhibitory synaptic inputs.

The results from this study provide the first evidence indicating that

activation of vanilloid type 1 (TRPV1) receptors

increases the neuronal activity of the dl-PAG

through selective potentiation

of glutamatergic synaptic inputs.


Toth et al 2005

Abstract – Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. atitoth@jaguar.unideb.hu

The vanilloid receptor (TRPV1 or VR1) is a molecular integrator of various painful stimuli, including capsaicin, acid, and high temperature. It can also be activated by endogenous ligands, like the cannabinoid 1 receptor (CB1) agonist anandamide.

vanilloid receptor (TRPV1 or VR1) is well characterized at the terminals of sensory nerves involved in the pain pathway.

There is also evidence that TRPV1 is expressed in the brain but little is known about its function. Here, using commercially available specific antibodies to investigate the localization of TRPV1 in the brain of the rat, we report that

vanilloid receptor (TRPV1 or VR1) was expressed in hippocampus, cortex, cerebellum, olfactory bulb, mesencephalon and hindbrain.

Immunohistochemical analyses showed high expression in the cell bodies and dendrites of neurons in the hippocampus and in the cortex.

To address the question of subcellular localization, immunoelectronmicroscopy was used. TRPV1-like staining was detected in the synapses (mostly, but not exclusively in post-synaptic dendritic spines), on the end feet of astrocytes and in pericytes.

In summary, vanilloid receptor (TRPV1 or VR1) expression shows wide distribution in the brain of the rat, being found in astrocytes and pericytes as well as in neurons. Its localization is consistent with multiple functions within the central nervous system, including the regulation of brain vasculature.


Medvedeva, Kim & Usachev 2008

Abstract – IA

J Neurosci. 2008 May 14;28(20):5295-311.


Mechanisms of prolonged presynaptic Ca2+ signaling and glutamate release induced by TRPV1 activation in rat sensory neurons.

Medvedeva YV, Kim MS, Usachev YM.

Transient receptor potential vanilloid receptor 1 (TRPV1)-mediated

….release of neuroactive peptides and neurotransmitters

…..from the peripheral and central terminals of primary sensory neurons

…..can critically contribute

…….to nociceptive processing at the periphery and in the CNS.

However, the mechanisms that link TRPV1 activation with Ca2+ signaling at the release sites and neurosecretion are poorly understood. Here we demonstrate that a brief stimulation of the receptor using either capsaicin or the

endogenous TRPV1 agonist N-arachidonoyl-


induces a prolonged elevation of presynaptic [Ca2+](i) and a

concomitant enhancement of

glutamate release at sensory synapses.

Initiation of this response required Ca2+ entry, primarily via TRPV1.

…..The sustained phase of the response was independent of extracellular Ca2+

.…..and was prevented by inhibitors of mitochondrial Ca2+ uptake and release mechanisms.

Measurements using a mitochondria-targeted Ca2+ indicator, mtPericam, revealed that TRPV1 activation elicits a long-lasting Ca2+ elevation in presynaptic mitochondria.

…..The concentration of TRPV1 agonist determined the duration of mitochondrial and cytosolic Ca2+ signals in presynaptic boutons and, consequently, the period of enhanced glutamate release and action potential firing by postsynaptic neurons.

These data suggest that

Mitochondria [i.e. genetics]

control vanilloid-induced neurotransmission

by translating the strength of presynaptic TRPV1 stimulation into duration of the postsynaptic response.


Sikand & Premkumar 2007

Abstract – IL

J Physiol. 2007 Jun 1;581(Pt 2):631-47. Epub 2007 Mar 15.


Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse.

Sikand P, Premkumar LS.

Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA.

Sensory input

from the periphery to the CNS

is critically dependent on the strength of synaptic transmission

at the first sensory synapse formed

between primary afferent dorsal root ganglion (DRG)

and superficial dorsal horn (DH) neurons

of the spinal cord.

Transient receptor potential vanilloid 1 (TRPV1)

….expressed on a subset of sensory neurons

…. plays an important role in chronic inflammatory thermal nociception.

Activation of protein kinase C (PKC)

sensitizes TRPV1,

which may contribute to the

pathophysiology of

chronic pain conditions.

Linda note:  Is TRPV1 involved at all in emotions, particularly sadness and/or fear?

Increased gain of sensory input by TRPV1-induced enhancement of glutamate release and its potentiation by various inflammatory mediators may contribute to persistent pain conditions.

………..Selective targeting of TRPV1 expressed on the central terminals of sensory neurons

……….may serve as a strategy

to alleviate

chronic intractable pain conditions.

See also:

TRPV1: A Target for Next Generation Analgesics.

Premkumar LS, Sikand P.

Curr Neuropharmacol. 2008 Jun;6(2):151-63.

PMID: 19305794 [PubMed – in process]

Related Articles Free article in PMC


Micale et al 2008

Abstract – Italy

1: Neuropsychopharmacology. 2009 Feb;34(3):593-606. Epub 2008 Jun 25.


Anxiolytic effects in mice of a dual blocker of fatty acid amide hydrolase and transient receptor potential vanilloid type-1 channels.

Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Drago F, Di Marzo V.

Department of Experimental and Clinical Pharmacology, University of Catania Medical School, Catania, Italy.

The endocannabinoid-inactivating enzyme,

fatty acid amide hydrolase (FAAH),

and the transient receptor potential vanilloid type-1 (TRPV1) channel are new targets for the development of

anxiolytic drugs.

We studied the effect on anxiety-like behavior in the elevated plus maze of a dual FAAH/TRPV1 blocker, N-arachidonoyl-serotonin (AA-5-HT). In male C57BL/6J mice, acute intraperitoneal administration of AA-5-HT (0.1-2.5 mg/kg) increased both the time spent and the number of entries in the open arm, while being inactive at the highest dose tested (5 mg/kg). AA-5-HT was more potent than selective blockers of FAAH or TRPV1 (URB597 and SB366791, respectively). In male Swiss mice, AA-5-HT had to be administered chronically to observe an anxiolytic effect at an intermediate dose (2.5 mg/kg), the highest dose (5 mg/kg) being anxiogenic, and 1 mg/kg being ineffective. In both strains, the

anxiolytic effects of AA-5-HT were paralleled

by elevation of brain endocannabinoid levels

and were reversed by per se inactive doses of the cannabinoid receptors of type-1 (CB(1)) receptor antagonist AM251, or the TRPV1 agonist, olvanil.

Immunohistochemical localization of CB(1) and TRPV1 receptors was observed in mouse

prefrontal cortex,

nucleus accumbens,

amygdala, and


Simultaneous ‘indirect’ activation of CB(1) receptors

following FAAH inhibition,

and antagonism at

TRPV1 receptors

might represent a new therapeutic strategy

against anxiety.

Linda note:  Here we are at the intersection of pain and anxiety.  If we lose something, we will find it in the last place we look.  Until modern times, we did not need to know the exact specifics of what made our body well or ill.  Nature took care of it for nearly all of us, automatically.  Those days are passing very rapidly into extinction.  We have to re-in-form ourselves, reform our understanding of ourselves, so that we can take responsibility consciously for what, until now, has always been going along just fine without our having to pay attention.


Chhatwal et al 2005

Neuropsychopharmacology. 2005 Mar;30(3):516-24.


Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear.

Chhatwal JP, Davis M, Maguschak KA, Ressler KJ.

Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Center for Behavioral Neuroscience, Yerkes Research Center, Atlanta, GA 30329, USA.

The endogenous cannabinoid (eCB) system represents a major therapeutic target for the treatment of a variety of anxiety-related disorders.

A recent study has demonstrated that pharmacologic or genetic disruption of CB1-receptor-mediated neurotransmission decreases the extinction of conditioned fear in mice.

Here, we examined whether CB1 blockade would similarly disrupt extinction in rats, using fear-potentiated startle as a measure of conditioned fear. We also examined whether pharmacologic enhancement of CB1 activation would lead to enhancements in extinction. Our results indicate that

…..systemic administration of the CB1 antagonist rimonabant (SR141716A) prior to extinction training led to significant, dose-dependent decreases in extinction.

While the administration of the CB1 agonist WIN 55,212-2 did not appear to affect extinction, administration of AM404, an inhibitor of eCB breakdown and reuptake, led to dose-dependent enhancements in extinction.

In addition to showing decreased fear 1 and 24 h after extinction training, AM404-treated animals showed decreased shock-induced reinstatement of fear.

… AM404 was acting to increase CB1 receptor activation during extinction training. These results demonstrate that the

eCB system can be modulated to enhance emotional learning,

and suggest that eCB modulators

….may be therapeutically useful as adjuncts for exposure-based psychotherapies such as those used to treat

Post-Traumatic Stress Disorder and other anxiety disorders.

But, again, how would these modulators be specific only to the area within the system that one wishes to access to treat anxiety disorders when the system is so widespread and affects so many aspects of the body’s functioning?


See also:

Neuropsychopharmacology. 2005 Mar;30(3):516-24.


Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear.

Chhatwal JP, Davis M, Maguschak KA, Ressler KJ.

Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Center for Behavioral Neuroscience, Yerkes Research Center, Atlanta, GA 30329, USA.

Psychopharmacology (Berl). 2007 Apr;191(2):223-31. Epub 2007 Jan 9.


The disruptive effects of the CB1 receptor antagonist rimonabant on extinction learning in mice are task-specific.

Niyuhire F, Varvel SA, Thorpe AJ, Stokes RJ, Wiley JL, Lichtman AH.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.


Varvel et al 2007

Neuropsychopharmacology. 2007 May;32(5):1032-41. Epub 2006 Oct 18.


Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task.

Varvel SA, Wise LE, Niyuhire F, Cravatt BF, Lichtman AH.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.

Recent reports have demonstrated that disruption of CB(1) receptor signaling impairs extinction of learned responses in conditioned fear

and Morris water maze paradigms.

Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption,

…………….but did exhibit a significant increase in the rate of extinction.

Unexpectedly, FAAH-compromised mice

……..also exhibited a significant increase in acquisition rate.

The CB(1) receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction.

Collectively, these results indicate that

endogenous anandamide plays a facilitatory role in extinction through a CB(1) receptor mechanism of action.

In contrast, the primary psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol, failed to affect extinction rates, suggesting that

FAAH is a more effective target than a direct acting CB(1) receptor agonist in facilitating extinction.

More generally, these findings suggest that FAAH inhibition

represents a promising pharmacological approach

to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors,

such as post-traumatic stress syndrome

and obsessive-compulsive disorder.

Linda note:  Well, this fits into my theory – they instantly go from the research and findings – to the creation of drug treatments.  There does not seem to be an interest in understanding for the sake of appreciating how things fit together, and how things influence one another.  It’s like a mad rush to the drug factory – and then to the drug candy store in the end —


See also:

Curr Opin Chem Biol. 2003 Aug;7(4):469-75.


Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system.

Cravatt BF, Lichtman AH.

The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. cravatt@scripps.edu

Neuropharmacology. 2008 Jan;54(1):141-50. Epub 2007 Jul 19.


Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors.

Moreira FA, Kaiser N, Monory K, Lutz B.

Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany.


Connell et al 2006

Neurosci Lett. 2006 Apr 24;397(3):180-4. Epub 2005 Dec 27.


Role of the basolateral nucleus of the amygdala in endocannabinoid-mediated stress-induced analgesia.

Connell K, Bolton N, Olsen D, Piomelli D, Hohmann AG.

Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, GA 30602-3013, USA.

Recent work in our laboratories has demonstrated that an

….opioid-independent form of stress-induced analgesia (SIA) is mediated by endogenous ligands for cannabinoid receptors-anandamide and 2-arachidonoylglycerol (2-AG) [Hofmann et al 2005]

The present study was conducted to examine the contribution of cannabinoid CB1 receptors in the basolateral nucleus of the amygdala (BLA) and central nucleus of the amygdala (CeA) to nonopioid SIA.

SIA was induced by continuous footshock (3 min 0.9 mA) and quantified behaviorally using the tail-flick test. Microinjection of the CB1 antagonist/inverse agonist rimonabant (SR141716A) into the

….BLA, a limbic forebrain region with high densities of CB1 receptors, suppressed SIA relative to control conditions. By contrast, the same dose administered into the

……CeA, where CB1 immunoreactivity is largely absent, or outside the amygdala did not alter SIA.

Our findings suggest that CB1 receptors in the BLA but not the CeA contribute to SIA, but

…….pharmacological inhibition of endocannabinoid degradation at these sites does not affect the expression of stress antinociception.


Gutierrez et al 2003

Brain Res. 2003 Oct 17;987(2):176-85.


Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinociception in models of acute and tonic nociception.

Gutierrez T, Nackley AG, Neely MH, Freeman KG, Edwards GL, Hohmann AG.

Neuroscience and Behavior Program, Department of Psychology, The University of Georgia, Athens, GA 30602, USA.

The effects of neurotoxic destruction of catecholaminergic projections

….to the spinal cord on cannabinoid antinociception were examined in models of acute and tonic nociception.

…The antinociceptive effect of WIN55,212-2 was attenuated relative to control conditions in rats depleted of spinal norepinephrine.

These data indicate that the suppressive effect of the cannabinoid on formalin-evoked Fos protein expression in the superficial dorsal horn was attenuated following destruction of descending noradrenergic pathways. Our data are consistent with the hypothesis that

cannabinoids produce antinociception, in part,

…..by modulating descending noradrenergic systems and support a ….differential involvement of

noradrenergic projections

…..to the spinal cord in cannabinoid modulation of acute versus tonic nociception.



Hofmann et al 2005

Nature. 2005 Jun 23;435(7045):1108-12.


An endocannabinoid mechanism for stress-induced analgesia.

Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D.

Neuroscience and Behavior Program, Department of Psychology, The University of Georgia, Athens, Georgia 30602-3013, USA. ahohmann@uga.edu

Acute stress

suppresses pain

by activating brain pathways

that engage opioid

or non-opioid mechanisms.

Here we show that an opioid-independent form of this phenomenon, ….termed stress-induced analgesia,

….is mediated by the release of endogenous marijuana-like ……(cannabinoid) compounds in the brain.

Blockade of cannabinoid CB(1) receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia.

In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol (2-AG) and anandamide.

So this IS a prime area for the interaction with PTSD!

A newly developed inhibitor of the 2-AG-deactivating enzyme, …..monoacylglycerol lipase,

…..selectively increases 2-AG concentrations

….and, when injected into the periaqueductal grey matter,

….enhances stress-induced analgesia in a CB1-dependent manner.

[Is this in humans or rats or what?] Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase, which selectively elevate anandamide concentrations, exert similar effects.

….. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia.

…..These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.


Suplita et al 2005

Neuropharmacology. 2005 Dec;49(8):1201-9. Epub 2005 Aug 29.


Inhibition of fatty-acid amide hydrolase enhances cannabinoid stress-induced analgesia: sites of action in the dorsolateral periaqueductal gray and rostral ventromedial medulla.

Suplita RL 2nd, Farthing JN, Gutierrez T, Hohmann AG.

Department of Psychology, Neuroscience and Behavior Program, University of Georgia, Athens, GA 30602-3013, USA.

Recent research in our laboratory has demonstrated that stress

activates an endogenous cannabinoid mechanism that suppresses sensitivity to pain [Nature 435 (2005) 1108].

In this work, CB(1) antagonists administered systemically blocked stress-induced analgesia induced by brief, continuous foot-shock. The present studies were conducted to examine the role of cannabinoid CB(1) receptors in the brainstem rostral ventromedial medulla (RVM) and midbrain dorsolateral periaqueductal gray (PAG) in cannabinoid stress-induced analgesia (SIA). Pharmacological blockade of vanilloid TRPV1 receptors with capsazepine, administered systemically, did not alter cannabinoid SIA, suggesting that cannabinoid SIA was not dependent upon TRPV1. Microinjection of the competitive CB(1) antagonist rimonabant (SR141716A) into either the RVM or dorsolateral PAG suppressed stress antinociception in this model. Rimonabant was maximally effective following microinjection into the dorsolateral PAG. The fatty-acid amide hydrolase (FAAH) inhibitor arachidonoyl serotonin (AA-5-HT) was subsequently used to block hydrolysis of endocannabinoids and enhance SIA. Systemic and site-specific injections of AA-5-HT into either the dorsolateral PAG or RVM induced CB(1)-mediated enhancements of SIA. Palmitoyltrifluoromethylketone, a potent inhibitor of FAAH and phospholipase A2 activity, administered systemically, exerted similar effects.

In all conditions, the antinociceptive effects of each FAAH inhibitor were completely blocked by coadministration of the CB(1) antagonist rimonabant. The present results provide evidence that

a descending cannabinergic neural system

is activated by environmental stressors

to modulate pain sensitivity in a CB(1)-dependent manner.


Hoffman 2007

Br J Pharmacol. 2007 Mar;150(6):673-5. Epub 2007 Feb 12.


Inhibitors of monoacylglycerol lipase as novel analgesics.

Hohmann AG.

Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, GA 30602-3013, USA. ahohmann@uga.edu

2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid (endocannabinoid) lipid whose functions remain poorly understood.

Guindon and colleagues report the novel finding that exogenous application of 2-AG induces peripheral antinociceptive effects that are mediated, at least in part, by actions at peripheral cannabinoid CB(2) receptors.

URB602, a recently described inhibitor of monoacylglycerol lipase, an enzyme that catalyzes 2-AG hydrolysis in vivo, also induced peripheral antinociceptive effects and enhanced the actions of 2-AG.

Peripheral analgesic mechanisms represent promising therapeutic targets for suppressing pain in the absence of unwanted central nervous system side-effects (e.g. psychoactivity) associated with activation of central CB(1) receptors.

The therapeutic potential of inhibitors of 2-AG deactivation for the treatment of inflammatory pain is discussed.

See also:

Phytother Res. 2008 Aug;22(8):1017-24.


Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved.

Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B.

Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.


Nackley AG, Suplita RL 2nd, Hohmann AG.  2003

Neuroscience. 2003;117(3):659-70.


A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation.

Nackley AG, Suplita RL 2nd, Hohmann AG.

Neuroscience and Behavior Program, Department of Psychology, The University of Georgia, Athens, GA 30602-3013, USA.

The present studies were conducted to test the hypothesis that systemically inactive doses of cannabinoids suppress inflammation-evoked neuronal activity in vivo via a peripheral mechanism. We examined peripheral cannabinoid modulation of spinal Fos protein expression, a marker of neuronal activity, in a rat model of inflammation. …These data provide

direct evidence that

…..a peripheral cannabinoid mechanism

…suppresses the development of inflammation-evoked neuronal activity

….at the level of the spinal dorsal horn and

….implicate a role for CB(2) and CB(1) in peripheral cannabinoid modulation of inflammatory nociception.


Barna et al 2007

Behav Pharmacol. 2007 Sep;18(5-6):515-20.


WIN-55,212-2 chronically implanted into the CA3 region of the dorsal hippocampus impairs learning: a novel method for studying chronic, brain-area-specific effects of cannabinoids.

Barna I, Soproni K, Arszovszki A, Csabai K, Haller J.

Institute of Experimental Medicine, Budapest, Hungary. barna@koki.hu

The memory-impairing effects of acute cannabinoid treatments are well known, but the effects of chronic treatments are controversial. The rate and magnitude of tolerance, however, have been shown to be brain-area specific and cell-type specific. Here we show that

chronic hippocampal treatments impair memory, suggesting that no tolerance develops in the hippocampus towards the memory-impairing effects of cannabinoids. The data also suggest that

chronic, brain-area-specific effects of cannabinoids can be studied by the novel method described here.


Balazsa et al 2008

Abstract – Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u. 43, Budapest 1083, Hungary. balazsat@ana.sote.hu

In the present study we investigated whether serotonin release in the hippocampus is subject to regulation via cannabinoid receptors. Both rat and mouse hippocampal slices …. Our data suggest that a subpopulation of non-synaptic serotonergic afferents express CB1 receptors and activation of these CB1 receptors leads to a decrease in 5-HT release.


Rubino et al 2008

Cereb Cortex. 2008 Jun;18(6):1292-301. Epub 2007 Oct 5.


Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex.

Rubino T, Realini N, Castiglioni C, Guidali C, Viganó D, Marras E, Petrosino S, Perletti G, Maccarrone M, Di Marzo V, Parolaro D.

In the present study we explored with a multidisciplinary approach, the

…. role of anandamide (AEA)

in the modulation of

anxiety behavior

at the level of the

prefrontal cortex (PFC).

Linda note:  Here we are at the intersection of the endogenous cannabinoid signaling system in the perception of anxiety – which means to me that this is where we detect that something is “not right” between ourselves and the world – either inside of us or in interaction with what is outside of us.

This is where “dis-ease” perception occurs, a deviation from “ease” or well-being.  Ill being must be attended to, one way or the other – and the anxiety can signal us that something is wrong, and then all the other systems have to find a way to fix the problem.  Modulation of anxiety behavior – as in, “How do we solve this problem and take care of what needs exist?”  Simply making the anxiety behavior go away without accomplishing anything useful as a result of it having been triggered in the first place would, to my thinking, be anti-evolutionarily suggested.  Nature is not stupid.

Low doses of the metabolically stable AEA analog, methanandamide, microinjected into the PFC, produced an anxiolytic-like response in rats,

whereas higher doses induced anxiety-like behaviors.

Yes, we do need to have it both ways!  Remember, we are a species named “The Wise Ones.’

Pretreatment with the selective antagonist of CB1 or TRPV1 receptors (AM251 and capsazepine, respectively) suggested that the anxiolytic effect evoked by AEA might be due to the interaction with the CB1 cannabinoid receptor,

whereas vanilloid receptors

….seem to be involved in AEA anxiogenic action.

When AEA contents in the PFC were increased

….by microinjecting the selective inhibitor of fatty acid amide hydrolase (FAAH), URB597,

….we observed an anxiolytic response only at low doses of the compound and no effect or even an anxiogenic profile at higher doses.

In line with this, a marked decrease of AEA levels in the PFC,

….achieved by lentivirus-mediated local overexpression of FAAH,

…..produced an anxiogenic response.

These findings support an

….anxiolytic role for physiological increases in AEA in the PFC,

whereas more marked increases due to

TRPV1 stimulation

or decreases due to lack of CB1 activation of this endocannabinoid

might lead to an anxiogenic response due to

TRPV1 stimulation – increases

or the lack of CB1 activation – decreases

in their words:

These findings support an anxiolytic role for physiological increases in AEA in the PFC, whereas more marked increases or decreases of this endocannabinoid might lead to an anxiogenic response due to TRPV1 stimulation or the lack of CB1 activation, respectively.



“A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses.  In pharmacology, antagonists have affinity but no efficacy for their cognate receptors and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to allosteric sites on receptors or they may interact at unique binding sites not normally involved in the biological regulation of the receptor’s activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex which in turn depends on the nature of antagonist receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors”

“An agonist is a term used to describe a type of ligand or drug that binds and alters the activity of a receptor. The ability to alter the activity of a receptor, also known as the agonist’s efficacy is a property that distinguishes it from antagonists, a type of receptor ligand which also bind a receptor but which do not alter the activity of the receptor. The efficacy of an agonist may be positive, causing an increase in the receptor’s activity or negative causing a decrease in the receptor’s activity.”


Rubino et al 2008b

Neuropharmacology. 2008 Jan;54(1):151-60. Epub 2007 Jul 6.


Erratum in:

Neuropharmacology. 2008 Aug;55(2):247.

CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour.

Rubino T, Guidali C, Vigano D, Realini N, Valenti M, Massi P, Parolaro D.

DBSF, Pharmacology Section and Center of Neuroscience, University of Insubria, via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy.


There is a general consensus that the effects

of cannabinoid agonists on anxiety

seem to be biphasic, with

low doses being anxiolytic and

high doses ineffective or possibly anxiogenic.

Besides the behavioural effects of cannabinoids on anxiety, very few papers have dealt with the neuroanatomical sites of these effects.

We investigated the effect on rat anxiety behavior of local administration of THC in the

prefrontal cortex,

basolateral amygdala and

ventral hippocampus,

brain regions belonging to the emotional circuit and containing high levels of CB1 receptors.

THC microinjected

……at low doses in the prefrontal cortex (10 microg) and ventral hippocampus (5 microg) induced in rats an anxiolytic-like response tested in the elevated plus-maze, whilst

…..higher doses lost the

anxiolytic effect

and even seemed to switch into an anxiogenic profile.

Low THC doses (1 microg) in the

basolateral amygdala produced an

anxiogenic-like response whereas

higher doses were ineffective.

All these effects were CB1-dependent

and closely linked to modulation of CREB [???] activation.

Specifically, THC anxiolytic activity in the prefrontal cortex and ventral hippocampus was paralleled by an increase in CREB activation,

…..whilst THC anxiogenic response in the basolateral amygdala was paralleled by a decrease in CREB activation.

Our results suggest that

….while a mild activation of CB1 receptors in the prefrontal cortex and ventral hippocampus attenuates [diminishes] anxiety,

…..a slight CB1 receptor stimulation in the amygdala results in an anxiogenic-like response.

The case being made that small amounts of stress stimulation actually have a calming effect?  Is this the central triggering point for the HPA axis disturbances being either hyper- or hypo- reactive?  This reminds me of the little boy with the trauma locked in his finger – the trigger finger – used when at age 4 he accidentally blew his brother’s head off.  Maybe this is the trigger point of our whole body!  Ground zero.  This is the epicenter of what quakes us, and where we quake.  It is the headwaters, the source, the king pin, the fountain head.

The molecular underpinnings of these effects involve a

………direct stimulation of CB1 receptors ending in pCREB modulation

………..and/or a possible alteration in the fine tuning of local neuromodulator release.


Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex.

Rubino T, Realini N, Castiglioni C, Guidali C, Viganó D, Marras E, Petrosino S, Perletti G, Maccarrone M, Di Marzo V, Parolaro D.

Cereb Cortex. 2008 Jun;18(6):1292-301. Epub 2007 Oct 5.

PMID: 17921459 [PubMed – indexed for MEDLINE]

Related Articles

Involvement of the endocannabinoid system in phencyclidine-induced cognitive deficits modelling schizophrenia.

Vigano D, Guidali C, Petrosino S, Realini N, Rubino T, Di Marzo V, Parolaro D.

Int J Neuropsychopharmacol. 2009 Jun;12(5):599-614. Epub 2008 Sep 15.

PMID: 18789179 [PubMed – in process]

Related Articles



An anxiolytic is a drug prescribed for the treatment of symptoms of anxiety

Haller et al 2004

Abstract – Hungary

CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents.

Haller J, Varga B, Ledent C, Freund TF.

Behav Pharmacol. 2004 Jul;15(4):299-304.

PMID: 15252281 [PubMed – indexed for MEDLINE]

Related Articles

Cannabinoids are

…known to modulate GABAergic – via CB1,

and glutamatergic transmission – latter via a novel receptor.

…..in cortical areas

Pharmacological data demonstrate that several widely used cannabinoid ligands bind to both receptors, which may explain the inconsistencies in their behavioural effects.

Earlier we showed that the cannabinoid antagonist SR-141716A

….affected behaviour in both CB1 knockout and wild-type animals, and its effect (anxiolysis) was different from that of

CB1 gene disruption


Linda note:  Ok, folks, this is getting spooky – again!  You mean people actually know this stuff?  This is the action of genesis, creation in progress, in process.  It brings to mind that song, “One way or the other…”  It makes me think of the “under toad” in “The World According to Garp.”  A riptide.  If we get enough stressors going at the same time, enough of our juggling balls in the air at the same time – each competing for a different adaptive, compensatory response, this must create all kinds of conflicts, one thing running into and over another – this seems to be more than allostatic load –

This would be the point of creation within us.  But these people DO NOT see the implications here.  They want to make and sell drugs – as if they are the savior of our species!

These responses have a place – literally have a place in our bodies where they originate – and a place in the natural order of life in that they have always served a purpose for us as a species – to survive and to adapt.


Palomo et al 2007

Neurotox Res. 2007 Jul;12(1):29-42.


Genetic variation and shared biological susceptibility underlying comorbidity in neuropsychiatry.

Palomo T, Kostrzewa RM, Beninger RJ, Archer T.

Psychiatry Service, 12 de Octubre, University Hospital, Madrid 28041, Spain.

Genetic factors underlying alcoholism, substance abuse, antisocial and violent behavior, psychosis, schizophrenia and psychopathy are emerging to implicate dopaminergic and cannabinoid, but also monoaminergic and glutamatergic systems through the maze of promoter genes and polymorphisms.

Candidate gene association studies suggest the involvement of a range of genes in different disorders of CNS structure and function. Indices of comorbidity both complicate the array of gene-involvement and provide a substrate of hazardous interactivity.

The putative role of the serotonin transporter gene in affective-dissociative spectrum disorders presents both plausible genetic variation and complication of comorbidity The position of genetic variation is further complicated through ethnic, contextual and social factors that provide geometric progressions in the comordity already underlying diagnostic obstacles. The concept of shared biological susceptibility to two or more disorder conditions of comorbidity seems a recurring observation, e.g., bipolar disorder with alcoholism or schizophrenia with alcohol/substance abuse or diabetes with schizopsychotic disorder.

Several lines of evidence seem to suggest that the factors influencing variation in one set of symptoms and those affecting one or more disorders are observed to a marked extent which ought to facilitate the search for susceptibility genes in comorbid brain disorders. Identification of regional genetic factors is awaited for a more compelling outline that ought eventually to lead to greater efficacy of symptom-disorder arrangements and an augmentation of current pharmacological treatment therapies.

See also:

Neurotox Res. 2004;6(5):343-61.


Gene-environment interplay in alcoholism and other substance abuse disorders: expressions of heritability and factors influencing vulnerability.

Palomo T, Kostrzewa RM, Beninger RJ, Archer T.

Servicio Psiquiátrico, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041 Madrid, Spain.


Xiong et al 2008

Mol Pharmacol. 2008 Feb;73(2):314-22. Epub 2007 Nov 9.


Anandamide inhibition of 5-HT3A receptors varies with receptor density and desensitization.

Xiong W, Hosoi M, Koo BN, Zhang L.

Laboratory for Integrative Neuroscience National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892, USA. lzhang@mail.nih.gov

Converging evidence has suggested that anandamide (AEA), an endogenous agonist of cannabinoid (CB) receptors, can directly interact with certain types of ligand-gated ion channels (LGICs).

However, little is known about the molecular and cellular mechanisms of AEA-induced direct effects on LGICs. Here, we report that AEA inhibited the function of serotoningated ion channels (5-HT(3A)) expressed in Xenopus laevis oocytes and human embryonic kidney 293 cells in a manner that was dependent on the steady-state receptor density at the cell surface. The magnitude of AEA inhibition was inversely correlated with the expression levels of receptor protein and function. …

The inhibition of 5-HT(3) receptors

by AEA may contribute

to its physiological roles in

control of pain and emesis.


Haller et al 2007

Eur J Neurosci. 2007 Apr;25(8):2445-56.


Correlated species differences in the effects of cannabinoid ligands on anxiety and on GABAergic and glutamatergic synaptic transmission.

Haller J, Mátyás F, Soproni K, Varga B, Barsy B, Németh B, Mikics E, Freund TF, Hájos N.

Institute of Experimental Medicine, Department of Behavioral Neurobiology, 1450 Budapest, PO Box 67, Hungary. haller@koki.hu

Cannabinoid ligands show therapeutic potential in a variety of disorders including anxiety. However,

the anxiety-related effects of cannabinoids remain controversial as agonists show opposite effects in mice and rats.

Cannabinoids affect both

GABAergic and

glutamatergic functions, which

play opposite roles in anxiety.

In rats, AM-251 potentiated this anxiogenic effect by inhibiting the anxiolytic GABAergic mechanism. We suggest that the

anxiety-related effects of cannabinoids

depend on the relative cannabinoid responsiveness of GABAergic and glutamatergic neurotransmission.


2 thoughts on “*Endocannabinoids, Pain, Depression and Grief

  1. Thank you for collecting so much research. It is helpful to me. And I believe your pages of experiences and opinions will be helpful to many. This is a good work. And stopping the intergenerational transmission of trauma is perhaps the most important thing that we can do for our culture.

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