Cited by 242Cannabis and Cannabinoid ResearchNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

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CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents

Haller, J., Varga, B., Ledent, C., Freund, T. F.·2004·Behavioural Pharmacology

DOI 10.1097/01.fbp.0000135704.56422.40

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Abstract

Cannabinoids are known to modulate GABAergic and glutamatergic transmission in cortical areas, the former via CB1 and the latter via a novel receptor. 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 (anxiogenesis). In the present experiments, we studied the effects of the CB1 antagonist AM-251, and the cannabinoid agonist WIN-55,212-2 in wild-type as well as in CB1 knockout mice. CB1 knockout mice showed higher scores of anxiety-like behaviour than the wild-type animals in the elevated plus-maze. Selective blockade of CB1 receptors by AM-251 (0.3, 1 and 3 mg/kg) increased anxiety-like behaviour dose-dependently in the wild-type mice but had no effect in the knockouts. In wild types, the cannabinoid agonist WIN-55,212-2 (1 and 3 mg/kg) caused a decrease in anxiety-like behaviour, which was abolished by the CB1-selective antagonist AM-251 (3 mg/kg). The same agonist did not change plus-maze behaviour in CB1 knockout animals. These data demonstrate at the behavioural level that AM-251 and, at low concentrations, WIN-55,212-2, are selective ligands of the CB1 cannabinoid receptor in mice. Our studies on the behavioural effects of the cannabinoid antagonist SR-141716A and the CB1 antagonist AM-251 show that the CB1 and the novel cannabinoid receptor mediate anxiolytic and anxiogenic effects, respectively. This suggests that agonists of the former, or antagonists of the latter, are promising new compounds in the pharmacotherapy of anxiety.

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“Thus, while the most widely used CB1 receptor antagonist rimonabant (SR141716A) has been found to have anxiolytic-like and/ or stress-inhibiting activity (Akinshola et al., 1999; Haller et al., 2002; Rodgers et al., 2003; DeGroot and Nomikos, 2004; Finn et al., 2004a; Haller et al., 2004; Griebel et al., 2005), there…”
BackgroundMethodResultInfluential
Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice
Umathe, S. N., Manna, S. S. S., & Jain, N. S. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.04.031 · Cited by 98
Cannabinoid receptor stimulation increases motivation for nicotine and nicotine seeking
Gamaleddin, I., Wertheim, C. E., Zhu, A. Z. X., Coen, K. M., Vemuri, K. V., Makryannis, A., Goldberg, S. R., & Foll, B. L. (2011) · Addiction Biology · doi:10.1111/j.1369-1600.2011.00314.x · Cited by 94
“In contrast, in rats the same compound produced the opposite effects (Haller et al. 2004).”
Background
Endocannabinoids in the Treatment of Mood Disorders: Evidence from Animal Models
Bambico, F. R., Duranti, A., Tontini, A., Tarzia, G., & Gobbi, G. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209788168029 · Cited by 94
“These receptors, as well as other yet unidentified ones, might therefore participate in the central and psychotropic effects of cannabinoids that are preserved in transgenic mice lacking CB1 [18-20].”
Background
The endocannabinoid system as a target for the treatment of cannabis dependence
Clapper, J. R., Mangieri, R. A., & Piomelli, D. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.07.018 · Cited by 94
“While some studies have reported anxiolytic- and antidepressant-like effects of CB1 receptor antagonists in rodents (Griebel et al., 2005; Haller et al., 2004; Shearman et al., 2003), others have shown that administration of these agents produces anxiogenic-like effects (Arévalo et al., 2001;…”
Background
Recent Progress in Understanding the Pathophysiology of Post-Traumatic Stress Disorder: Implications for Targeted Pharmacological Treatment
Bailey, C. R., Cordell, E., Sobin, S. M., & Neumeister, A. (2013) · CNS Drugs · doi:10.1007/s40263-013-0051-4 · Cited by 89
“cological disruption of CB1 receptor signalling, which is required for normal fear extinction [121–123], results in an anxious PTSD phenotype [126, 127], and brain CB1 receptor signalling controls extinction of aversive memo-”
Background
The endocannabinoid and endovanilloid systems interact in the rat prelimbic medial prefrontal cortex to control anxiety-like behavior
Fogaça, M. V., de Aguiar, D. C., Moreira, F. A., & Guimarães, F. S. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.03.007 · Cited by 89
Cannabinoid-related Agents in the Treatment of Anxiety Disorders: Current Knowledge and Future Perspectives
Tambaro, S., & Bortolato, M. (2011) · Recent Patents on CNS Drug Discovery · doi:10.2174/157488912798842269 · Cited by 93
“In agreement with human evidence, preclinical studies have elucidated that the acute administration of low doses of CB1 receptor agonists elicits anxiolytic-like in approach/avoidance tasks [152-156]; conversely, high concentrations of the same compounds are generally associated with the opposite outcomes [157-162] (f…”
Result
Endocannabinoid-mediated modulation of stress responses: Physiological and pathophysiological significance
Finn, D. P. (2009) · Immunobiology · doi:10.1016/j.imbio.2009.05.011 · Cited by 91
“These mice exhibit an anxiogenic profile in the elevated plusmaze (Haller et al., 2002; Haller et al., 2004b; Uriguen et al., 2004) (but see also Houchi et al., 2005; Ledent et al., 1999; Marsicano et al., 2002), the light-dark box (Maccarrone et al., 2002; Martin et al., 2002; Uriguen et al.,…”
Influential
Potential anxiogenic effects of cannabinoid CB1 receptor antagonists/inverse agonists in rats: Comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG-7142
Sink, K. S., Segovia, K. N., Sink, J. R., Randall, P. A., Collins, L. E., Correa, M., Markus, E. J., Vemuri, K. V., Makriyannis, A., & Salamone, J. D. (2009) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2009.11.002 · Cited by 89
“These results are consistent with previous studies of CB1 inverse agonists (Arevalo et al., 2001; McGregor et al., 1996; Navarro et al., 1997; Rodriguez de Fonseca et al., 1996), including studies with AM251 in mice (Haller et al., 2004; Rodgers et al., 2005).”
BackgroundResultInfluential
Endocannabinoids, cannabinoids and the regulation of anxiety
Petrie, G. N., Nastase, A. S., Aukema, R. J., & Hill, M. N. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108626 · Cited by 91
Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake
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Chapter 5 The Endocannabinoid System as A Target for Novel Anxiolytic and Antidepressant Drugs
Gaetani, S., Dipasquale, P., Romano, A., Righetti, L., Cassano, T., Piomelli, D., & Cuomo, V. (2009) · International Review of Neurobiology · doi:10.1016/s0074-7742(09)85005-8 · Cited by 83
Interaction between cannabinoid compounds and diazepam on anxiety-like behaviour of mice
Naderi, N., Haghparast, A., Saber-Tehrani, A. S., Rezaii, N., Alizadeh, A.-M., Khani, A., & Motamedi, F. (2007) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2007.11.001 · Cited by 87
Role of Endocannabinoid Signaling in Anxiety and Depression
Patel, S., & Hillard, C. J. (2009) · Current topics in behavioral neurosciences · doi:10.1007/978-3-540-88955-7_14 · Cited by 91
“A second CB1 receptor antagonist, AM251, a structural analog of rimonabant, also shows anxiogenic effects in rodents in the elevated plus maze (Haller et al. 2004b; Patel and Hillard 2006).”
BackgroundInfluential
The effects of trauma on brain and body: A unifying role for the midbrain periaqueductal gray
Terpou, B. A., Harricharan, S., McKinnon, M. C., Frewen, P., Jetly, R., & Lanius, R. A. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24447 · Cited by 82
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McLaughlin, R. J., & Gobbi, G. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.07.052 · Cited by 84
ROLE OF DORSAL HIPPOCAMPAL CANNABINOID RECEPTORS AND NITRIC OXIDE IN ANXIETY LIKE BEHAVIOURS IN RATS USING THE ELEVATED PLUS‐MAZE TEST
Roohbakhsh, A., Moghaddam, A. H., Massoudi, R., & Zarrindast, M. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04576.x · Cited by 82
“Although this drug has been reported to be a selective CB1 receptor antagonist, some studies have suggested that part of the pharmacological effects of SR141716A may be mediated through blockade of a third cannabinoid receptor.(37) Additional complexities are suggested by the failure of this drug to block the anxiogen…”
Background
Substance use modulates stress reactivity: Behavioral and physiological outcomes
Fosnocht, A. Q., & Briand, L. A. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.02.024 · Cited by 80
The cannabinoid CB 1 receptor and the endocannabinoid anandamide: possible antidepressant targets
Bambico, F. R., & Gobbi, G. (2008) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.12.11.1347 · Cited by 80
CB1 knockout mice display impaired functionality of 5‐HT1A and 5‐HT2A/C receptors
Mato, S., Aso, E., Castro, E., Martín, M., Valverde, O., Maldonado, R. J., & Pazos, Á. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04961.x · Cited by 80
“Reminiscent of the 5-HT1A receptor knockout phenotype, CB1 receptor knockout mice also display increased levels of anxiety in different behavioral paradigms (Martı́n et al. 2002; Haller et al. 2004; Urigüen et al. 2004).”
Background
Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder
Neumeister, A., Seidel, J., Ragen, B., & Pietrzak, R. H. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.10.012 · Cited by 76
“Genetic or pharmacological disruption of CB1 receptor signaling results in anxiety phenotypes (Haller et al., 2002, Haller et al., 2004).”
Background
Evaluation of the emotional phenotype and serotonergic neurotransmission of fatty acid amide hydrolase-deficient mice
Cassano, T., Gaetani, S., Macheda, T., Laconca, L., Romano, A., Morgese, M. G., Cimmino, C. S., Chiarotti, F., Bambico, F. R., Gobbi, G., et al. (2011) · Psychopharmacology · doi:10.1007/s00213-010-2051-0 · Cited by 72
Cannabinoid modulation of noradrenergic circuits: Implications for psychiatric disorders
Carvalho, A. F., & Bockstaele, E. J. V. (2012) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.01.008 · Cited by 72
“Generally, the anxiogenic properties of cannabinoid agents occur more frequently in drug-naïve subjects and in novel/stressful environments (Degroot, 2008; Haller et al., 2004a; Viveros et al., 2005).”
Background
Enhancement of endocannabinoid signaling and the pharmacotherapy of depression
Mangieri, R. A., & Piomelli, D. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2007.09.003 · Cited by 73
Endocannabinoids suppress excitatory synaptic transmission to dorsal raphe serotonin neurons through the activation of presynaptic CB1 receptors.
Haj-Dahmane, S., & Shen, R.-Y. (2009) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.153858 · Cited by 69
“Genetic deletion or pharmacological blockade of CB1 receptors increases anxiety related behavioral responses (Arévalo et al., 2001; Haller et al., 2004).”
Background
Facilitation of CB1 receptor-mediated neurotransmission decreases marble burying behavior in mice
Gomes, F. V., Casarotto, P. C., Resstel, L. B. M., & Guimarães, F. S. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.11.027 · Cited by 69
“The drug dose range was based on previous results from the literature (Haller et al., 2004; Rutkowska et al., 2006).”
Modulation of Fear and Anxiety by the Endogenous Cannabinoid System
Chhatwal, J. P., & Ressler, K. J. (2007) · CNS Spectrums · doi:10.1017/s1092852900020939 · Cited by 71
“Similar results have been acquired using pharmacologic antagonists of the CB1-receptor, suggesting that the anxiety phenotype seen in CB1 knockouts is unlikely due to developmental consequences.(10) Notably, however, increased anxiety has more consistently”
Result
Altering endocannabinoid neurotransmission at critical developmental ages: impact on rodent emotionality and cognitive performance
Trezza, V., Campolongo, P., Manduca, A., Morena, M., Palmery, M., Vanderschuren, L. J. M. J., & Cuomo, V. (2012) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2012.00002 · Cited by 69
Endocannabinoid System and Exogenous Cannabinoids in Depression and Anxiety: A Review
Hasbi, A., Madras, B. K., & George, S. R. (2023) · Brain Sciences · doi:10.3390/brainsci13020325 · Cited by 69
Altered CB1receptor‐signaling in prefrontal cortex from an animal model of depression is reversed by chronic fluoxetine
Rodríguez‐Gaztelumendi, A., Rojo, M. L., Pazos, Á., & Díaz, Á. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05898.x · Cited by 68
“CB1 receptor knockout mice exhibited enhanced anxiety- and depressive-like behaviors (Haller et al. 2002; Martin et al. 2002; Haller et al. 2004; Uriguen et al. 2004).”
Background
Cannabinoid Receptor Antagonists Counteract Sensorimotor Gating Deficits in the Phencyclidine Model of Psychosis
Ballmaier, M., Bortolato, M., Rizzetti, M. C., Zoli, M., Gessa, G., Heinz, A., & Spano, P. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301344 · Cited by 65
“Both rimonabant and AM251 are known to act as CB1 inverse agonists at relatively high doses (see, eg, Haller et al, 2004), raising the possibility that some of the observed results may not simply depend on CB1 blockade.”
Background
The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System
Berger, A. L., Henricks, A. M., Lugo, J. M., Wright, H. R., Warrick, C. R., Sticht, M. A., Morena, M., Río, I. B., Laredo, S. A., Craft, R. M., et al. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.04.018 · Cited by 66
“Moreover, systemic CB1R blockade usually increases anxiety-like behaviors (24–26), particularly under stressful conditions (21).”
Background
Effect of chronic exposure to rimonabant and phytocannabinoids on anxiety-like behavior and saccharin palatability
Schurman, L. D., Wills, K. L., Segsworth, B. M., Dashney, B., Rock, E. M., Limebeer, C. L., & Parker, L. A. (2012) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2012.10.008 · Cited by 66
The endocannabinoid system in the regulation of emotions throughout lifespan: a discussion on therapeutic perspectives
Marco, E. M., & Laviola, G. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111408459 · Cited by 67
“Data from both genetic and pharmacological blockade of CB1Rs are controversial, since conflicting results have also been reported (Haller et al., 2004a, 2004b; Marsicano et al., 2002).”
Result
Cannabinoid Modulation of the Stressed Hippocampus
Scarante, F. F., Vila-Verde, C., Lopes, V. D., Ferreira‐Junior, N. C., Guimarães, F. S., & Campos, A. C. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00411 · Cited by 66
“Other studies, however, using CB1 receptor-deficient animals or CB1 antagonist, revealed increased defensive responses only under high aversive conditions (Haller et al., 2004a; de Oliveira Alvares et al., 2005; Jacob et al., 2009).”
BackgroundResult
Enhancement of endocannabinoid signalling during adolescence: Modulation of impulsivity and long-term consequences on metabolic brain parameters in early maternally deprived rats
Marco, E. M., Adriani, W., Canese, R., Podo, F., Viveros, M., & Laviola, G. (2006) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2006.10.006 · Cited by 62
The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice
Mikics, É., Dombi, T., Barsvári, B., Varga, B., Ledent, C., Freund, T., & Haller, J. (2006) · Behavioural Pharmacology · doi:10.1097/00008877-200605000-00003 · Cited by 61
“The doses selected were similar to those found earlier to be behaviorally active in various tests, including those related to anxiety (Haller et al., 2002, 2004a, b; Shearman et al., 2003; Chambers et al., 2004; Drews et al., 2005; Pascual et al., 2005; Rodgers et al., 2005).”
BackgroundMethodInfluentialSelf-citation
The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats
Need, A. B., Davis, R. J., Alexander-Chacko, J. T., Eastwood, B. J., Chernet, E., Phebus, L. A., Sindelar, D. K., & Nomikos, G. G. (2005) · Psychopharmacology · doi:10.1007/s00213-005-0234-x · Cited by 61
“1998), neuroprotection (reviewed in Grundy 2002), and anxiety (Haller et al. 2004).”
Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved?
Moreira, F. A., de Aguiar, D. C., Campos, A. C., Lisboa, S. F. D. S., Terzian, A. L. B., Resstel, L. B. M., & Guimarães, F. S. (2008) · Neural Plasticity · doi:10.1155/2009/625469 · Cited by 62
“WIN-55212 EPM 1–3 mg/kg (mouse) [51]”
Effects of the Cannabinoid-1 Receptor Antagonist Rimonabant on Psychiatric Symptoms in Overweight People With Schizophrenia
Kelly, D. L., Gorelick, D. A., Conley, R. R., Boggs, D. L., Linthicum, J., Liu, F., Feldman, S. M., Ball, M. P., Wehring, H. J., McMahon, R. P., et al. (2010) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e318204825b · Cited by 59
Increased sensitivity of adolescent spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder, to the locomotor stimulation induced by the cannabinoid receptor agonist WIN 55,212-2
Pandolfo, P., Pamplona, F. A., Prediger, R. D., & Takahashi, R. N. (2007) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.02.013 · Cited by 58
Effects of Δ9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic unpredictable stress
Fokos, S., & Panagis, G. (2009) · Journal of Psychopharmacology · doi:10.1177/0269881109104904 · Cited by 57
The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats
Shallcross, J., Hámor, P. U., Bechard, A. R., Romano, M., Knackstedt, L. A., & Schwendt, M. (2019) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2019.00091 · Cited by 61
“However, CB1 agonists can also produce biphasic anxiogenic and anxiolytic effects (Haller et al., 2004; Sink et al., 2010), which may compromise their clinical usefulness.”
Background
An endocannabinoid signaling system modulates anxiety-like behavior in male Syrian hamsters
Moise, A. M., Eisenstein, S. A., Astarita, G., Piomelli, D., & Hohmann, A. G. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1209-5 · Cited by 55
“Mice lacking CB1 receptors are prone to anxiety-like and depression-like behaviors (Haller et al. 2002, 2004a, b; Maccarrone et al. 2002).”
Background
The Endocannabinoid System and Anxiety
Lisboa, S. F. D. S., Gomes, F. V., Terzian, A. L. B., de Aguiar, D. C., Moreira, F. A., Resstel, L. B. M., & Guimarães, F. S. (2016) · Vitamins and hormones · doi:10.1016/bs.vh.2016.09.006 · Cited by 56
Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies
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Psychostimulant Effect of the Synthetic Cannabinoid JWH-018 and AKB48: Behavioral, Neurochemical, and Dopamine Transporter Scan Imaging Studies in Mice
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Exploiting the Multifaceted Effects of Cannabinoids on Mood to Boost Their Therapeutic Use Against Anxiety and Depression
Bassi, M. S., Gilio, L., Maffei, P., Dolcetti, E., Bruno, A., Buttari, F., Centonze, D., & Iezzi, E. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00424 · Cited by 51

Authors: Haller, J., Varga, B., Ledent, C., & Freund, T. F.
Affiliations: HUN-REN Institute of Experimental Medicine (HU)
Université Libre de Bruxelles (BE)
Corresponding author: Haller, J.
ORCID: Haller, J.
Varga, B.
Ledent, C.
Freund, T. F.
Venue: Behavioural Pharmacology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2004-07
Volume: 15
Issue: 4
Pages: 299-304
ISSN: 0955-8810 (ISSN-L)
DOI: 10.1097/01.fbp.0000135704.56422.40
OpenAlex: W2009732294
Cited by: 241
References: 49
Citations by year: 2026: 3 · 2025: 12 · 2024: 4 · 2023: 12 · 2022: 5 · 2021: 9 · 2020: 8 · 2019: 7 · 2018: 8 · 2017: 7 · 2016: 6 · 2015: 9 · 2014: 9 · 2013: 13 · 2012: 15
FWCI: 8.79
Type: journal article
Language: en
Open access: closed
Locations: Behavioural Pharmacology (publishedVersion)
PubMed (publishedVersion)
Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
Funders: National Institute of Mental Health (R01MH054671, MH54671)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: CB1 receptor, anxiolytic effects, anxiety-like behavior, CB1 knockout mice, AM251, WIN 55,212-2, SR141716A, CB1 agonists, elevated plus maze, GABAergic neurotransmission, glutamatergic neurotransmission
MeSH terms: Rimonabant, Animals, Behavior, Animal, Dose-Response Relationship, Drug, Drug Synergism, Male, Morpholines, Naphthalenes, Piperidines, Pyrazoles, Anti-Anxiety Agents, Mice, Knockout, Maze Learning, Receptor, Cannabinoid, CB1, Benzoxazines, Mice

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CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents

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