Vol. 292, Issue 2, 714-724, February 2000

D₁ Dopamine Receptor Agonists Are More Effective in Alleviating Advanced than Mild Parkinsonism in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Monkeys¹

Martin Goulet and Bertha K. Madras

Harvard Medical School, New England Regional Primate Research Center, Division of Neurochemistry, Southborough, Massachusetts.

Selective D₁ dopamine receptor agonists exert antiparkinsonian effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's disease and in human Parkinson's disease. Motor impairment in idiopathic Parkinson's disease progresses from mild to severe, but the therapeutic potential of D₁ dopamine receptor agonists in early and advanced stages of parkinsonism is not known. To compare the effectiveness of D₁ agonists at different levels of impairment, we developed a model of mild and advanced parkinsonism in nonhuman primates and a rating scale that differentiated the two models. D₁ dopamine receptor agonists (SKF 81297, dihydrexidine) and D₂ 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), SKF 81297 and dihydrexidine did not promote increased motor activity. In advanced parkinsonism (n = 4), D₁ and D₂ dopamine agonists effectively reversed the motor deficits. In contrast, the therapeutic benefits of D₁ agonists SKF 81297 and dihydrexidine were relatively limited in mild parkinsonism (n = 4). The D₂ agonists quinelorane and (+)-PHNO alleviated some symptoms in mild parkinsonism but also reduced balance and induced more dyskinesias than did D₁ agonists. Mild and advanced parkinsonism in nonhuman primates can be produced with fixed dosing regimens of MPTP. Based on the therapeutic efficacy and side effect profiles derived from these models, D₁ agonists are more promising for the treatment of advanced than of mild Parkinson's disease.