Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-na??ve and plus-maze-experienced mice

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’.