Blockade of cannabinoid (CB1) receptors by SR 141716 selectively antagonizes drug-induced reinstatement of exploratory behaviour in gerbils

Rationale: A cannabinoid hypothesis of schizophrenia has been proposed acco rding to which cognitive dysfunction could be associated with dysregulation of an endogenous cannabinoid system. Objective: The present study investig ated whether SR 141716, a selective CB1 receptor antagonist, was able to re duce the hyperactivity induced in gerbils by various stimulant drugs known to produce or exacerbate schizophrenic symptoms. Methods: Cocaine, d-amphet amine, morphine,and Win 55212-2 were administered intraperitoneally (TP) ei ther immediately before placing the animals in the test apparatus (non-habi tuated gerbils) or after a 2- to 3-h habituation period in the actimeter (h abituated gerbils). SR 141716 was given IP 30 min before the injection of s timulant drugs. Horizontal activity was recorded every 10 min for 1 h in Di giscan activity monitor. Results: SR 141716 (0.3-3 mg/kg) dose-dependently suppressed the enhanced locomotor activity induced by each stimulant drug i n habituated gerbils, but not in non-habituated animals. Clozapine, an atyp ical antipsychotic compound, but not haloperidol, shared with SR 141716, th e ability to differentially affect drug-induced hyperactivity in habituated versus non-habituated gerbils. Conclusion: The activation of cannabinoid s ystems is a required, permissive element in the ability of cocaine, d-amphe tamine, morphine, and Win 55212-2 to reinstate behaviour, i.e., to override stimulus satiation.