Several clinical studies have shown that alterations in the cannabinoid system in the brain may be associated with schizophrenia. Although evidence points towards an antipsychotic potential for cannabinoid antagonists, experimental studies have shown inconsistent behavioural effects of cannabinoid ligands within and across species. The aim of the present study was to explore these contradictory findings in a non-human primate model, predictive of antipsychotic efficacy in humans. The effects of the cannabinoid CB1 receptor antagonist SR141716A and the CB1 receptor agonist CP55,940 were explored in an d-amphetamine-based Cebus monkey model of psychosis. The monkeys were sensitive to extrapyramidal side effects (EPS), and the side-effect profiles of the drugs were explored as well. SR141716A (0.1, 0.25, 0.375, 0.5 and 0.75mg/kg) and CP55,940 (0.0025, 0.005 and 0.01mg/kg) were administered by subcutaneous injection alone and in combination with d-amphetamine (0.25mg/kg). SR141716A (0.1–0.5mg/kg) reduced d-amphetamine-induced arousal, while CP55,940 had no significant effect upon d-amphetamine-induced behaviours. No EPS were observed with either of these compounds. These data suggest that cannabinoid CB1 antagonists such as SR141716A may have limited antipsychotic potential in man as to positive symptoms. SR141716A administered alone induced anxiolytic-like behaviour, whereas administration of CP55,940 alone showed anxiogenic properties.
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