Partial and full dopamine D 1 receptor agonists in mice and rats: relation between behavioural effects and stimulation of adenylate cyclase activity in vitro

Abstract

The dopamine (DA) D 1 agonists, SK&F 83959, SK&F 75670, SK&F 38993, SK&F 81297 and SK&F 80723, had variable abilities to stimulate adenylate cyclase activity in rat striatal homogenates. Their efficacies, in relation to the effect of 100 μM DA were 0, 33, 69, 68 and 81%, respectively. In rats, all compounds induced (1) contralateral circling behaviour after unilateral 6-hydroxy-DA lesions, (2) ipsilateral circling behaviour after midbrain hemitransection after cotreatment with the D 2 agonist quinpirole and (3) oral stereotypies after their combination with quinpirole. Maximum effects and rank order of potencies were similar in the three test models. In mice SK&F 83959, SK&F 75670 and SK&F 38393 inhibited methylphenidate-induced gnawing behaviour and induced no or only weak hypermotility. SK&F 81297 induced marked hypermotility which was partially inhibited by SK&F 83959 and SK&F 75670 and was completely blocked by the D 1 antagonist, SCH 23390. It is concluded that no relation could be demonstrated between the efficacy to stimulate adenylate cyclase and to induce circling behaviours and stereotypies in rats. In contrast, a relation between biochemical and behavioural efficacies was found in the mouse models. The results suggest that different subtypes of D 1 receptors mediate the behavioural effects reported in this study.