Abstract

Studies were undertaken to clarify further the mechanism(s) of action of the atypical neuroleptic clozapine, using a behavioural model with the ability to distinguish between relative antagonism of D1 vs. D2 dopamine receptor-mediated function. Pretreatment with low doses of clozapine (2.5-25.0 mg/kg) readily antagonised intense grooming induced by the selective D1 agonist SK&F 77434 (0.75 mg/kg), and in a less consistent manner antagonised hyperactivities induced by the selective D2 agonist LY 163502 (0.05 mg/kg). In animals whose typical responses to SK&F 77434 were antagonised by clozapine, no atypical behaviours such as vacuous chewing emerged. However, in animals whose typical responses to LY 163502 were antagonised by clozapine, a syndrome of atypical limb/body jerking was released. Despite clozapine showing comparable affinities for D1 and D2 receptors in vitro, this behavioural profile shows similarities to that seen when these agonists are given after pretreatment with a selective D1 antagonist, rather than with a selective D2 antagonist or with non-selective neuroleptics. These results suggest that clozapine has some preferential though not selective action in vivo to antagonise D1 dopamine receptor-mediated function.