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Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naïve and plus-maze-experienced mice.
Behav Pharmacol 2005; 16(5-6):405-13BP

Abstract

The notoriously inconsistent effects of cannabinoids on anxiety-like behaviour may be explained by recent research on CB1 receptor knockout (CB1-KO) mice suggesting that cannabinoids exert bidirectional effects via the CB1 receptor (anxiolysis) and a novel rimonabant-sensitive neuronal cannabinoid receptor (anxiogenesis). This hypothesis is supported by the anxiogenic-like profile of AM-251, an analogue of rimonabant that is a potent and selective CB1 receptor antagonist but which, unlike rimonabant, has no activity at the novel receptor. As we have previously shown that rimonabant reduces anxiety-like behaviour in test-experienced animals only, the current study assessed the effects of AM-251 (1.5-3.0 mg/kg) in male Swiss-Webster mice that were either plus-maze-naïve or had been exposed undrugged to the apparatus 24 h prior to testing. Results confirmed that prior maze experience per se significantly increases behavioural indices of anxiety without altering measures of general activity. In maze-naïve mice, the lower dose of AM-251 (1.5 mg/kg) significantly reduced % open-arm time and increased grooming while the higher dose (3.0 mg/kg) additionally reduced open-arm entries and total head-dipping, and increased closed-arm returns. These anxiogenic-like effects were observed in the absence of significant changes in general activity levels. Although AM-251 had a very similar profile in maze-experienced animals, significant drug effects on open-arm avoidance measures were precluded by experientially-induced changes in behavioural baselines (i.e. 'ceiling' effects). Nevertheless, AM-251 again significantly reduced total head-dipping and increased grooming (3.0 mg/kg) and, unlike effects in naïve animals, both doses markedly reduced time spent on the centre platform and increased time spent in the enclosed arms. Against a baseline of almost total open-arm avoidance, the pattern of behavioural change in maze-experienced mice would also be consistent with an anxiogenic-like action of AM-251. Data are discussed in relation to previous findings with rimonabant, the putative existence of a novel non-CB1 neuronal cannabinoid receptor and, more generally, the behavioural pharmacology of plus-maze 'trial 2'.

Authors+Show Affiliations

Behavioural Neuroscience Laboratory, Institute of Psychological Sciences, University of Leeds, England, UK. r.j.rodgers@leeds.ac.ukNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

16148445

Citation

Rodgers, R J., et al. "Anxiogenic Profile of AM-251, a Selective Cannabinoid CB1 Receptor Antagonist, in Plus-maze-naïve and Plus-maze-experienced Mice." Behavioural Pharmacology, vol. 16, no. 5-6, 2005, pp. 405-13.
Rodgers RJ, Evans PM, Murphy A. Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naïve and plus-maze-experienced mice. Behav Pharmacol. 2005;16(5-6):405-13.
Rodgers, R. J., Evans, P. M., & Murphy, A. (2005). Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naïve and plus-maze-experienced mice. Behavioural Pharmacology, 16(5-6), pp. 405-13.
Rodgers RJ, Evans PM, Murphy A. Anxiogenic Profile of AM-251, a Selective Cannabinoid CB1 Receptor Antagonist, in Plus-maze-naïve and Plus-maze-experienced Mice. Behav Pharmacol. 2005;16(5-6):405-13. PubMed PMID: 16148445.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naïve and plus-maze-experienced mice. AU - Rodgers,R J, AU - Evans,P M, AU - Murphy,A, PY - 2005/9/9/pubmed PY - 2006/1/10/medline PY - 2005/9/9/entrez SP - 405 EP - 13 JF - Behavioural pharmacology JO - Behav Pharmacol VL - 16 IS - 5-6 N2 - The notoriously inconsistent effects of cannabinoids on anxiety-like behaviour may be explained by recent research on CB1 receptor knockout (CB1-KO) mice suggesting that cannabinoids exert bidirectional effects via the CB1 receptor (anxiolysis) and a novel rimonabant-sensitive neuronal cannabinoid receptor (anxiogenesis). This hypothesis is supported by the anxiogenic-like profile of AM-251, an analogue of rimonabant that is a potent and selective CB1 receptor antagonist but which, unlike rimonabant, has no activity at the novel receptor. As we have previously shown that rimonabant reduces anxiety-like behaviour in test-experienced animals only, the current study assessed the effects of AM-251 (1.5-3.0 mg/kg) in male Swiss-Webster mice that were either plus-maze-naïve or had been exposed undrugged to the apparatus 24 h prior to testing. Results confirmed that prior maze experience per se significantly increases behavioural indices of anxiety without altering measures of general activity. In maze-naïve mice, the lower dose of AM-251 (1.5 mg/kg) significantly reduced % open-arm time and increased grooming while the higher dose (3.0 mg/kg) additionally reduced open-arm entries and total head-dipping, and increased closed-arm returns. These anxiogenic-like effects were observed in the absence of significant changes in general activity levels. Although AM-251 had a very similar profile in maze-experienced animals, significant drug effects on open-arm avoidance measures were precluded by experientially-induced changes in behavioural baselines (i.e. 'ceiling' effects). Nevertheless, AM-251 again significantly reduced total head-dipping and increased grooming (3.0 mg/kg) and, unlike effects in naïve animals, both doses markedly reduced time spent on the centre platform and increased time spent in the enclosed arms. Against a baseline of almost total open-arm avoidance, the pattern of behavioural change in maze-experienced mice would also be consistent with an anxiogenic-like action of AM-251. Data are discussed in relation to previous findings with rimonabant, the putative existence of a novel non-CB1 neuronal cannabinoid receptor and, more generally, the behavioural pharmacology of plus-maze 'trial 2'. SN - 0955-8810 UR - https://www.unboundmedicine.com/medline/citation/16148445/Anxiogenic_profile_of_AM_251_a_selective_cannabinoid_CB1_receptor_antagonist_in_plus_maze_naïve_and_plus_maze_experienced_mice_ L2 - http://Insights.ovid.com/pubmed?pmid=16148445 DB - PRIME DP - Unbound Medicine ER -