Selective dopamine antagonist pretreatment on the antiparkinsonian effects of benzazepine D1 dopamine agonists in rodent and primate models of Parkinson's disease--the differential effects of D1 dopamine antagonists in the primate.

Abstract

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, pretreatment with the D1 DA antagonists, SCH 23390 (7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepin e) and A66359 (1- 2-bromo-4,5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2-methyl- 1,2,3,4 tetrahydroisoquinoline), but not the D2 DA antagonist raclopride inhibited the contralateral circling induced by the benzazepine D1 DA agonists SKF 38393 (7-H, 3-H analogue of SCH 23390), SKF 80723 (7-H, 3-H, 6-Br analogue) and SKF 83959 (7-H, 6-Cl, 3'-CH3 analogue). In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of SKF 80723 and SKF 83959 increased locomotor activity and reversed the motor disability. Grooming and oral activities were also increased. Pretreatment with SCH 23390 and A66359 inhibited all the behavioural changes induced by both D1 DA agonists. In general, higher doses of A66359 and more especially SCH 23390 were needed to inhibit SKF 83959 and SKF 80723 induced increases in oral activity and grooming than locomotor activity. Raclopride pretreatment did not affect SKF 83959 and SKF 80723 induced oral activity and grooming, though it reduced the duration of the locomotor changes induced by the D1 DA agonists. These findings demonstrate that the behavioural effects of benzazepine D1 DA agonists in the 6-OHDA lesioned rat and MPTP-treated marmoset are mediated by D1 DA receptor sites, although in the primate, stimulation of D2 DA receptors by endogenous DA may be necessary in facilitating the antiparkinsonian effects of D1 DA agonists. The differential sensitivities of locomotor/motor disability and oral/grooming behaviours to antagonism by D1 DA antagonists may indicate the involvement of multiple D1 DA receptor subtypes in mediating benzazepine D1 DA agonist induced behaviours in the MPTP-treated marmoset.