THE DIFFERENTIAL BEHAVIORAL-EFFECTS OF BENZAZEPINE D-1 DOPAMINE AGONISTS WITH VARYING EFFICACIES, CO-ADMINISTERED WITH QUINPIROLE IN PRIMATE AND RODENT MODELS OF PARKINSONS-DISEASE

The effects of co-administration of quinpirole with benzazepine D-1 do pamine (DA) agonists possessing full/supramaximal (SKF 80723 and SKF 8 2958), partial (SKF 38393 and SKF 75670) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) were investigated in rodent and primate models of Parkinson's disease (PD). In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, co- administration of SKF 38393 oxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83 959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 82958 (6-Cl, 3-C3H5 analogu e) strongly potentiated the contralateral circling induced by quinpiro le. In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated com mon marmosets, administration of quinpirole alone increased locomotor activity and reversed motor deficits. Grooming and oral activity were unaltered. Go-administration of SKF 38393 and SKF 75670 inhibited the quinpirole-induced changes in locomotor activity and motor disability. The combined treatment of SKF 80723 or SKF 82958 with quinpirole had no overall effect on locomotor activity or motor disability. In contra st, SKF 83959 extended the duration of the quinpirole-induced increase in locomotor activity with corresponding decreases in motor disabilit y. Go-administration of high doses of SKF 82958 and more especially SK F 83959 and SKF 80723, with quinpirole induced hyperexcitability and s eizures. Oral activity and grooming were unaltered following the co-ad ministration of benzazepine derivatives with quinpirole. The ability o f some benzazepine D-1 DA agonists to prolong the antiparkinsonian eff ects of quinpirole in the MPTP-treated marmoset may indicate a role fo r certain D-1 DA agonists in the clinical treatment of PD. In general, the behavioural responses to the combined administration of benzazepi nes with quinpirole in the 6-OHDA lesioned rat and more especially the MPTP-treated marmoset failed to correlate with their ability to stimu late AC. These observations further implicate a behavioural role for D -1 DA receptors not linked to AC.