Synergistic interaction between dopamine D-1 and D-2 receptor agonists: circling behaviour of rats with hemitransection

Abstract

Circling behaviour induced by dopamine (DA) agonists with different D-1/D-2 receptor selectivity was studied in rats with hemitransection at a level caudal to the striatum. The mixed D-1/D-2 agonist apomorphine induced ipsilateral circling behaviour after administration of doses similar to those that induced stereotyped behaviour in unlesioned rats. The effect of apomorphine was not influenced by co-treatment with SK & F 38393 or quinpirole, indicating that apomorphine induces a comparable D-1 and D-2 receptor stimulation in vivo also. Three selective D-1 agonists, SK & F 38393, SK & F 75670 and Lu 24-040 had no effects alone, while the preferential D-2 agonists quinpirole, pergolide and (−)-N-propylnorapomorphine induced ipsilateral circling of weaker intensity than did apomorphine. After co-treatment with SK & F 38393 the effects of these compounds were markedly increased. Combination of SK & F 38393, SK & F 75670 or Lu 24-040 with quinpirole induced circling with intensities similar to those seen after apomorphine. Pretreatment with the D-1 antagonist SCH 23390 or the D-2 antagonist YM 09151-2 completely antagonized the ipsilateral circling induced by either apomorphine or quinpirole + SK & F 38393. A range of partial (autoreceptor) D-2 agonists, i.e. (−)-3-PPP, (+)-3-phenethyl-PP, terguride, EMD 23448 and B-HT 920 were all ineffective as was the α 2-adrenoceptor agonist clonidine. However, B-HT 920 induced strong ipsilateral circling after combination with SK & F 38393, whereas (−)-3-PPP was ineffective. Our results indicate that stimulation of both D-1 and postsynaptic D-2 receptors is necessary for the expression of circling behaviour which is mediated in this model by postsynaptic DA receptors in the intact hemisphere, i.e. normosensitive receptors. Both D-1 or D-2 antagonists blocked the circling behaviour, showing that both receptor types must contribute. This also suggests that the weak activity of D-2 agonists on their own depends on some endogenous D-1 receptor stimulation. Finally, the equal effect obtained with combinations of quinpirole and SK & F 38393, SK & F 75670 or Lu 24-040, which have different abilities to stimulate adenylate cyclase activity in vitro (18–67% of the maximal effect of DA), suggests the presence of a large receptor reserve at D-1 receptors involved in the regulation of motor activity.