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

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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.

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