Abstract
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 D1agonists 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.
Footnotes
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Send reprint requests to: Dr. B. K. Madras, Department of Psychiatry, Harvard Medical School, New England Regional Primate Research Center, Division of Neurochemistry, One Pine Hill Dr., Southborough, MA 01772-9102. E-mail: bertha_madras{at}hms.harvard.edu
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↵1 This work was supported in part by National Institutes of Health Grants NS30556, DA09462, DA00304, and RR00168. M.G. is the recipient of a postdoctoral training fellowship from the Medical Research Council of Canada. Some results have been presented in abstract form [Goulet M and Madras BK (1998) Efficacy of a dopamine D1 receptor agonist depends on severity of parkinsonism. Soc Neurosci Abstr24:303.3].
- Abbreviations:
- MPTP
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- PHNO
- 4-propyl-9-hydroxy-2,3,4a,5,6,10b-hexahydro-4H-naphth[1,2b][1,4]oxazine
- Received August 17, 1999.
- Accepted November 10, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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