Relative Dopamine D1 and D2 Receptor Affinity and Efficacy Determine Whether Dopamine Agonists Induce Hyperactivity or Oral Stereotypy in Rats

Abstract

The effects of a range of dopamine (DA) agonists on stereotyped behaviour in rats were analysed and compared both with the affinity of the compounds for D₁ and D₂ receptor binding sites in vitro and their ability to stimulate the adenylate cyclase activity in rat striatal homogenates. Full and partial agonists at the D₁ receptor coupled toadenylate cyclase do not induce stereotypies when given alone, whereas full D₂ agonists (e.g. quinpirole) induce hyperactivity but not oral stereotypies. Partial D₂ agonists (e.g. (—)-3-PPP) only induce sedation. Mixed D₁/D₂ agonists (e.g. apomorphine) induce both hyperactivity and oral stereotypies. Maximum stereotypies were induced by combination of SK & F 38393 and a series of D₂ agonists, including full agonists and the partial D₂ agonist B-HT 920, whereas partial agonists with low intrinsic activity (e.g. (-)-3-PPP, EMD 23448) did not induce stereotypies when given together with SK & F 38393. However, these partial agonists reduced the maximum effect of apomorphine, whereas the full agonists (e.g. quinpirole, (—)-NPA) and B-HT 920 had no apomorphine antagonistic activity. The mixed D₁/D₂ agonists apomorphine and N,N-dipropyl-5,6-ADTN were only weakly influenced by SK & F 38393, or not at all. D₁ agonists with central effects, including SK & F 38393, SK & F 81297 (with relatively high efficacies), and the partial agonist SK & F 75670 with low efficacy, changed the hyperactivity induced by quinpirole into maximum oral stereotypy, whereas the peripheral D₁ agonist fenoldopam had no such effect. Inhibition of DA and NA synthesis with α-methyl-p-tyrosine depleted striatal DA levels by 72 per cent and antagonized the hyperactivity induced by the D₂ agonists quinpirole and (—)-NPA, but not that of apomorphine. Combination of SK & F 38393 and quinpirole induced maximum stereotypy in DA-depleted animals. These results suggest that D₁ receptor tonus is a necessary prerequisite for the expression of a DA agonist's effect. The hyperactivity induced by full D₂ agonists appears to be mediated by D₁ tonus provided by endogenous DA activity, but stronger D₁ stimulation is necessary to induce oral stereotypy. A high degree of D₁ receptor activation increases the ability of partial D₂ agonists to induce hyperactivity or oral stereotypies since treatment with both SK & F 38393 and B-HT 920 had marked effects while B-HT 920 was ineffective. The behavioural stimulation induced by a particular DA agonist thus depends on relative D₁/D₂ receptor affinity and also on the intrinsic activity at D₂ receptors, while intrinsic activity at D₁ receptors appears to be less important. The relative importance of D₁ and D₂ receptors for expression of different stereotypy patterns is useful for in vivo evaluation of the selectivity ratios of DA agonists.