D-1 dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys

Selective D-1 dopamine receptor agonists exert antiparkinsonian effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Par kinson's disease and in human Parkinson's disease. Motor impairment in idio pathic Parkinson's disease progresses from mild to severe, but the therapeu tic potential of D1 dopamine receptor agonists in early and advanced stages of parkinsonism is not known. To compare the effectiveness of D-1 agonists at different levels of impairment, we developed a model of mild and advanc ed parkinsonism in nonhuman primates and a rating scale that differentiated the two models. D-1 dopamine receptor agonists (SKF 81297, dihydrexidine) and D-2 dopamine receptor agonists [quinelorane, (+)-PHNO were administered to monkeys (Macaca fascicularis) displaying either mild parkinsonism (two doses of 0.6 mg/kg i.v. MPTP 1 month apart) or advanced parkinsonism (three doses of 0.6 mg/kg i.v. MPTP within 10 days). In normal monkeys (n = 3), S KF 81297 and dihydrexidine did not promote increased motor activity. In adv anced parkinsonism (n = 4), D-1 and D-2 dopamine agonists effectively rever sed the motor deficits. In contrast, the therapeutic benefits of D-1 agonis ts SKF 81297 and dihydrexidine were relatively limited in mild parkinsonism (n = 4). The D-2 agonists quinelorane and (+)-PHNO alleviated some symptom s in mild parkinsonism but also reduced balance and induced more dyskinesia s than did D-1 agonists. Mild and advanced parkinsonism in nonhuman primate s can be produced with fixed dosing regimens of MPTP. Based on the therapeu tic efficacy and side effect profiles derived from these models, D-1 agonis ts are more promising for the treatment of advanced than of mild Parkinson' s disease.