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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Background
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Self-citation
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Background
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“Among them, the different experimental context/conditions, the drug selectivity, the vehicle used for drug dissolution and the time of administration are of crucial importance (Haller et al., 2004a; Varga et al., 2008; Campolongo et al., 2012, 2013; KrukSlomka et al., 2016b).”
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“These mice weighed approximately 35 g. Housing conditions were similar to those described for CB1-KOs and WTs.”
BackgroundResultInfluentialSelf-citation
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Background
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Background
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BackgroundSelf-citation
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“…activity, exploration or food-handling ability, comparable doses (1–8 mg/kg) of the compound have been found to increase anxiety-like behaviour (e.g. Haller et al., 2004; Rodgers et al., 2005), elicit gaping (rejection) reactions in the taste reactivity test (McLaughlin et al., 2005; Jarrett et…”
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Background
The cannabinoid receptor CB1 inverse agonist AM251 potentiates the anxiogenic activity of urocortin I in the basolateral amygdala
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Background
Study the Effect of Endocannabinoid System on Rat Behavior in Elevated Plus-Maze.
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BackgroundMethodInfluential
Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats
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BackgroundResult
A comprehensive review of the multifaceted role of cannabinoid receptor type 2 in neurodegenerative and neuropsychiatric disorders
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Method
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“Nonetheless, observations that even sub-anorexigenic doses of typical CB1R inverse agonists such as rimonabant can affect the behavior of experimental animals in ways suggestive of human affective disorders [184-191] suggest that it might be difficult to quantify and attain a degree of CNS gating that ensures CB1R inv…”
Background
Intracerebroventricular administration of cannabinoid CB1 receptor antagonists AM251 and AM4113 fails to alter food-reinforced behavior in rats
Sink, K. S., Segovia, K. N., Nunes, E. J., Collins, L. E., Vemuri, K. V., Thakur, G. A., Makriyannis, A., & Salamone, J. D. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1602-8 · Cited by 28
“2007), and also may differ in terms of actions on novel uncharacterized non-CB1 receptors (Haller et al. 2002; Hajos et al. 2001; Haller et al. 2004).”
Background
Cannabinoid-1 receptors in the mouse ventral pallidum are targeted to axonal profiles expressing functionally opposed opioid peptides and contacting N-acylphosphatidylethanolamine-hydrolyzing phospholipase D terminals
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“Endocannabinoid signaling seems to be indispensable for the adequate coping of the organism with aversive and stressful situations (64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76).”
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“Further support for this effect emerged from studies using CB1 receptor knockout mice, which showed increased anxiogenic responses in the light–dark box, EPM, and social interaction tests (Haller et al., 2002, 2004; Martin et al., 2002; Urigüen et al., 2004).”
Background
The role of the endocannabinoid system in autism spectrum disorders: Evidence from mouse studies
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“Impaired sociability [123] and social exploration [114, 115] was observed in these KOs (although they seemed dependent on the testing context [84] and the type of social stimulus [116]), as well as altered social memory”
Background
Development of an Indole-Amide-Based Photoswitchable Cannabinoid Receptor Subtype 1 (CB 1 R) “Cis-On” Agonist
Rodríguez‐Soacha, D. A., Steinmüller, S. A. M., Işbilir, A., Fender, J., Deventer, M. H., Ramírez, Y. A., Tutov, A., Sotriffer, C., Stove, C. P., Lorenz, K., et al. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00160 · Cited by 23
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“Furthermore, CB1 inverse agonists have been shown to induce behavioral signs of anxiety (Arevalo et al., 2001; Haller et al., 2004; McGregor et al., 1996; Navarro et al., 1997; Rodgers et al., 2005), and a depression-like state in animals (Beyer et al.”
Background
Nicotine-induced anxiety-like behavior in a rat model of the novelty-seeking phenotype is associated with long-lasting neuropeptidergic and neuroplastic adaptations in the amygdala: Effects of the cannabinoid receptor 1 antagonist AM251
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“In line with the clinical findings, anxiogenic-like effects of CB1R antagonism have been reported in rodents (Arévalo et al., 2001; McGregor et al., 1996; Navarro et al., 1997; Haller et al., 2004; Rodgers et al., 2005).”
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Effects of Δ 9 -THC and Type-1 Cannabinoid Receptor Agonists in the Elevated Plus Maze Test of Anxiety: A Systematic Review and Meta-Analysis
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“Albeit the test was validated pharmacologically for anxiety, it is quite different from the rest of the tests and elicits complex behavioral responses which may explain the anxiolytic-like effect of CB1 gene disruption in its case.”
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Investigating the role of CB1 endocannabinoid transmission in the anti-fear and anxiolytic-like effects of ventromedial prefrontal cortex deep brain stimulation
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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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