CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents
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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These CB1 receptor adaptations give rise to an anxious/depressive phenotype.
“which in turn give rise to an anxious/depressive phenotype20, 21.”
From Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study (2013) · cites this paper as [21]
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“Conversely, CB1 receptor antagonists SR141716 (rimonabant) and AM251 produce anxiogenic-like effects in rodents (Navarro et al, 1997; Haller et al, 2004; Rodgers et al, 2005), and rimonabant increases the incidence of anxiety and depression in clinical trials for the treatment of obesity (Samat et…”
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“Interestingly, the disruption of the CB1 receptor gene (knockout models) was found to increase anxiety, whereas a pharmacological blockade of the receptor had anxiolytic effects [98,99].”
BackgroundImpaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice
Steiner, M. A., Wanisch, K., Monory, K., Marsicano, G., Borroni, E., Bächli, H., Holsboer, F., Lutz, B., & Wotjak, C. T. (2007) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500466 · Cited by 123 · see citing works
Novelty and Anxiolytic Drugs Dissociate Two Components of Hippocampal Theta in Behaving Rats
Wells, C. E., Amos, D. P., Jeewajee, A., Douchamps, V., Rodgers, J., O'Keefe, J. M., Burgess, N., & Lever, C. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5040-12.2013 · Cited by 116 · see citing works
“CB1 receptor agonists (especially at low doses) are anxiolytic (Haller et al., 2004).”
Casarotto, P. C., Terzian, A. L. B., Aguiar, D. C., Zangrossi, H., Guimarães, F. S., Wotjak, C. T., & Moreira, F. A. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.207 · Cited by 117 · see citing works
“At the behavioral level, CB1 knockout mice show deficits in extinction and habituation of conditioned fear (Kamprath et al, 2006; Marsicano et al, 2002) and exacerbated anxiety-like behavior (Haller et al, 2002, 2004; Jacob et al, 2009; Martin et al, 2002).”
BackgroundModulation of the serotonin system by endocannabinoid signaling
Haj‐Dahmane, S., & Shen, R. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.02.016 · Cited by 117 · see citing works
“In addition, behavioral studies using CB1 knock out mice or pharmacological blockers of CB1 receptor have shown an increase in stress-related behaviors (Haller et al., 2004a,b).”
CB1 Cannabinoid Receptor Signaling and Biased Signaling
Leo, L. M., & Abood, M. E. (2021) · Molecules · doi:10.3390/molecules26175413 · Cited by 117 · see citing works
“CB1 agonists have also been shown to reduce anxiety-like behavior [27,28] and depressive-like behavior [29,30] in preclinical models, showing promise for the treatment of generalized anxiety and major depression disorders.”
BackgroundYoshida, T., Uchigashima, M., Yamasaki, M., Katona, I., Yamazaki, M., Sakimura, K., Kano, M., Yoshioka, M., & Watanabe, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012875108 · Cited by 116 · see citing works
“The amygdala plays critical roles in associative processes of aversive emotions (9), and intake of cannabinoids elicits dose-dependent and biphasic effects on emotionality (10, 11).”
BackgroundBraida, D., Limonta, V., Malabarba, L., Zani, A. D., & Sala, M. (2006) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2006.10.038 · Cited by 115 · see citing works
Neuropsychiatric Adverse Effects of Centrally Acting Antiobesity Drugs
Nathan, P. J., O’Neill, B. V., Napolitano, A., & Bullmore, E. T. (2010) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2010.00172.x · Cited by 113 · see citing works
“Consistent with the proposed neurochemical mechanism, CB1 knockout mice have been shown to have increased anxiety in several animal models of anxiety [104–107] and also show profound deficits in the learned inhibition of fear (i.”
BackgroundPavón, F. J., Bilbao, A., Hernández‐Folgado, L., Cippitelli, A., Jagerovic, N., Abellán, G., Rodrı́guez-Franco, M. I., Serrano, A., Macías, M., de Heras, R. G., et al. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.03.029 · Cited by 113 · see citing works
Hill, M. N., & Patel, S. (2013) · Biology of Mood & Anxiety Disorders · doi:10.1186/2045-5380-3-19 · Cited by 117 · see citing works
“elevated plus-maze [18-22], novelty-induced hypophagia assay [23], social interaction test [24], light–dark box assay [25] and ultrasonic vocalization assay [26].”
MethodMoreira, F. A., de Aguiar, D. C., Terzian, A. L. B., Guimarães, F. S., & Wotjak, C. T. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.08.046 · Cited by 112 · see citing works
Llorente‐Berzal, A., Terzian, A. L. B., Marzo, V. D., Micale, V., Viveros, M., & Wotjak, C. T. (2015) · Psychopharmacology · doi:10.1007/s00213-015-3917-y · Cited by 107 · see citing works
“…between aversiveness of the test situation and involvement of the endocannabinoid/endovanilloid system in the regulation of fear and anxiety (Haller et al. 2004; Marsch et al. 2007; Naidu et al. 2007; Morena et al., 2014), including the expression of conditioned fear (Kamprath et al. 2009;…”
BackgroundQin, Z., Zhou, X. C., Pandey, N. R., Vecchiarelli, H. A., Stewart, C. A., Zhang, X., Lagace, D. C., Brunel, J. M., Béïque, J.-C., Stewart, A. F. R., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.02.015 · Cited by 105 · see citing works
“…eCB Signaling Interestingly, the anxiety and fear extinction phenotypes in LMO4KO mice look strikingly similar to those observed in CB1 receptor knockout (KO) mice (Haller et al., 2004; Marsicano et al., 2002), so we sought to determine whether eCB function was altered in LMO4KO mice.”
BackgroundHaller, J., Mátyás, F., Soproni, K., Varga, B., Barsy, B., Németh, B., Mikics, É., Freund, T. F., & Hájos, N. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05476.x · Cited by 103 · see citing works
“It has been shown that mice are sensitive to cannabinoid effects only when the plus-maze is brightly lit (Haller et al., 2004a).”
BackgroundMethodInfluentialSelf-citationThe Clinical Implications of Mouse Models of Enhanced Anxiety
Sartori, S. B., Landgraf, R., & Singewald, N. (2011) · Future Neurology · doi:10.2217/fnl.11.34 · Cited by 97 · see citing works
Rodgers, R. J., Evans, P., & Murphy, A. (2005) · Behavioural Pharmacology · doi:10.1097/00008877-200509000-00013 · Cited by 98 · see citing works
“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…”
BackgroundMethodResultInfluentialInvolvement 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 96 · see citing works
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 92 · see citing works
“In contrast, in rats the same compound produced the opposite effects (Haller et al. 2004).”
BackgroundEndocannabinoids 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 91 · see citing works
“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].”
BackgroundThe 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 92 · see citing works
“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;…”
BackgroundBailey, C. R., Cordell, E., Sobin, S. M., & Neumeister, A. (2013) · CNS Drugs · doi:10.1007/s40263-013-0051-4 · Cited by 89 · see citing works
“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-”
BackgroundFogaça, 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 · see citing works
Tambaro, S., & Bortolato, M. (2011) · Recent Patents on CNS Drug Discovery · doi:10.2174/157488912798842269 · Cited by 89 · see citing works
“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…”
ResultFinn, D. P. (2009) · Immunobiology · doi:10.1016/j.imbio.2009.05.011 · Cited by 88 · see citing works
“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.,…”
InfluentialSink, 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 86 · see citing works
“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).”
BackgroundResultInfluentialEndocannabinoids, 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 85 · see citing works
Serrano, A., Pavon, F. J., Buczynski, M. W., Schlosburg, J., Natividad, L. A., Polis, I. Y., Stouffer, D. G., Zorrilla, E. P., Roberto, M., Cravatt, B. F., et al. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0055-3 · Cited by 83 · see citing works
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 · see citing works
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 85 · see citing works
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 85 · see citing works
“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).”
BackgroundInfluentialThe 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 · see citing works
Cannabinoids and emotionality: a neuroanatomical perspective
McLaughlin, R. J., & Gobbi, G. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.07.052 · Cited by 82 · see citing works
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 · see citing works
“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…”
BackgroundSubstance 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 · see citing works
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 · see citing works
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 79 · see citing works
“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).”
BackgroundNeumeister, A., Seidel, J., Ragen, B., & Pietrzak, R. H. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.10.012 · Cited by 76 · see citing works
“Genetic or pharmacological disruption of CB1 receptor signaling results in anxiety phenotypes (Haller et al., 2002, Haller et al., 2004).”
BackgroundCassano, 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 · see citing works
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 · see citing works
“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).”
BackgroundEnhancement 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 71 · see citing works
Haj-Dahmane, S., & Shen, R.-Y. (2009) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.153858 · Cited by 69 · see citing works
“Genetic deletion or pharmacological blockade of CB1 receptors increases anxiety related behavioral responses (Arévalo et al., 2001; Haller et al., 2004).”
BackgroundFacilitation 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 · see citing works
“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 70 · see citing works
“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”
ResultTrezza, 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 68 · see citing works
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 68 · see citing works
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 · see citing works
“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).”
BackgroundBallmaier, 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 · see citing works
“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.”
BackgroundBerger, 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 · see citing works
“Moreover, systemic CB1R blockade usually increases anxiety-like behaviors (24–26), particularly under stressful conditions (21).”
BackgroundSchurman, 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 · see citing works
Marco, E. M., & Laviola, G. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111408459 · Cited by 65 · see citing works
“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).”
ResultCannabinoid 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 64 · see citing works
“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).”
BackgroundResultMarco, E. M., Adriani, W., Canese, R., Podo, F., Viveros, M., & Giovanni Laviola, A. (2006) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2006.10.006 · Cited by 62 · see citing works
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 · see citing works
“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).”
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“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 61 · see citing works
“WIN-55212 EPM 1–3 mg/kg (mouse) [51]”
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 · see citing works
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“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.”
BackgroundAn 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 · see citing works
“Mice lacking CB1 receptors are prone to anxiety-like and depression-like behaviors (Haller et al. 2002, 2004a, b; Maccarrone et al. 2002).”
BackgroundThe 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 · see citing works
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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 49 · see citing works
- 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.
- Venue
- Behavioural Pharmacology
- Published
- 2004-07
- Volume
- 15
- Issue
- 4
- Pages
- 299-304
- ISSN
- 0955-8810 (ISSN-L)
- 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 › 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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