Dopamine D-2 agonists with high and low efficacies: differentiation by behavioural techniques

Abstract

The effects of the dopamine (DA) D-2 antagonist YM 09151-2 and the DA D-2 agonists terguride, preclamol, EMD 23448, B-HT 920, quinpirole and (-)-NPA were studied in a battery of behavioural tests in order to evaluate their relative efficacies. Furthermore, their affinities for DA D-2 receptors labelled by 3H-N-0437 were measured in vitro. All agonists reduced spontaneous locomotor activity and induced marked contralateral circling behaviour in 6-hydroxy-DA-lesioned rats. Quinpirole and (-)-NPA increased motor activity after high doses. YM 09151-2 did not induce circling. In hemitransected rats quinpirole and (-)-NPA had weak effects when given alone, whereas the other agonists were ineffective. After combination with DA D-1 agonist SK&F 38393, B-HT 920 became effective, and the effects of quinpirole and (-)-NPA were facilitated. EMD 23448, preclamol and terguride were not active. In contrast, the two latter compounds fully inhibited the response to apomorphine. In stereotypy experiments a similar activity pattern was observed. Finally, drug discrimination studies showed that quinpirole, (-)-NPA and B-HT 920 substituted for the stimulus effects induced by d-amphetamine or (-)-NPA in different groups of rats. EMD 23448 induced intermediate effects, whereas preclamol and terguride had weak effects. None of the partial agonists inhibited the response of d-amphetamine. YM 09151-2 potently inhibited the effect of d-amphetamine. The results suggest that DA D-2 agonists can be ranked according to gradually increasing agonist efficacies rather than classified into autoreceptor-selective versus nonselective D-2 agonists. Implications of this hypothesis are discussed.