The effects of clozapine on behavioural responses to the selective ‘D1‐like’ dopamine receptor agonist, A 68930, and to the selective ‘D2‐like’ agonist, RU 24213

Abstract

The influence of the atypical antipsychotic clozapine on D1 dopamine receptor‐mediated function was examined in terms of its effects on behavioural responses to the new isochroman selective D1 agonist, A 68930, and to the selective D2 agonist, RU 24213. In rat striatal membrane preparations, radioligand binding studies with [3H]‐SCH 23390 and [3H]‐spiperone confirmed clozapine to show weak and non‐selective affinity for both D1 and D2 receptors. Using a rapid time‐sampling behavioural check list technique, clozapine (4.0–36.0 mg kg−1) exerted only modest antagonism of RU 24213 (15.0 mg kg−1)‐induced sniffing and locomotion, and weakly released some episodes of myoclonic jerking; such antagonism with release of jerking has been shown previously to occur only during concurrent stimulation of D2 receptors and attenuation of D1 function. Over the same dose‐range, clozapine completely blocked A68930 (0.25 mg kg−1)‐induced intense grooming but failed to influence the vacuous chewing response; this profile was similar to that demonstrated previously for selective D1 antagonists. On the basis of complete blockade of typical D1 agonist‐induced grooming and weak release of atypical jerking to D2 agonism in the face of modest reduction in typical D2‐stimulated behaviours, clozapine apears to exert some preferential but not selective attenuation of D1 receptor‐mediated function. Clozapine may attenuate activity through a classical D1 receptor at a level beyond the recognition site, for which it has little affinity, or by way of new, putative ‘Dplike’ site(s) that subserve distinct elements of dopaminergic behaviour. 1994 British Pharmacological Society