The interaction of clozapine with dopamine D 1 versus dopamine D 2 receptor-mediated function: behavioural indices

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 D 1 vs. D 2 dopamine receptor-mediated function. Pretreatment with low doses of clozapine (2.5–25.0 mg/kg) readily antagonised intense grooming induced by the selective D 1 agonist SK&F 77434 (0.75 mg/kg), and in a less consistent manner antagonised hyperactivities induced by the selective D 2 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 D 1 and D 2 receptors in vitro, this behavioural profile shows similarities to that seen when these agonists are given after pretreatment with a selective D 1 antagonist, rather than with a selective D 2 antagonist or with non-selective neuroleptics. These results suggest that clozapine has some preferential though not selective action in vivo to antagonise D 1 dopamine receptor-mediated function.