Abstract
The mechanisms underlying actions of dihydroxyphenylalanine (l-DOPA) in Parkinson's disease remain to be fully elucidated. Noradrenaline formed from l-DOPA may stimulate α1-adrenoceptors. We assessed the involvement of α1-adrenoceptors in actions of l-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques. In each animal, the minimal dose of l-DOPA required to alleviate parkinsonian symptoms was defined (12.5–25 mg/kg p.o.). The effects of coadministration of the α1-adrenoceptor antagonist prazosin ([4-(4-amino-6,7-dimethoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone) on motor activity, parkinsonism, and dyskinesia were assessed. Antiparkinsonian benefit was accompanied by mild dyskinesia. l-DOPA also elicited hyperactivity, i.e., activity greater than that seen in normal animals. Coadministration of prazosin (0.16–0.63 mg/kg p.o.) with l-DOPA did not significantly affect either its antiparkinsonian actions or dyskinesia. However, prazosin significantly and dose-dependently attenuated l-DOPA-induced activity, reducing it to a level equivalent to that of normal animals. More specifically, during periods of pronounced l-DOPA-induced activity, prazosin attenuated the total and duration of activity by 80 and 76%, respectively. These actions of prazosin were expressed in the absence of sedation. Although activation of α1-adrenoceptors plays no major role in the antiparkinsonian and dyskinetic effects of l-DOPA per se, it does contribute to the induction of hyperactivity. α1-Adrenoceptors may be involved in pathological responses to l-DOPA treatment, including the dopamine dysregulation syndrome.
Footnotes
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This work was supported by the Krembil Neuroscience Fund [Grant 252002] and by the Cure Parkinson's Trust [Grant CPTJB1].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.144097.
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ABBREVIATIONS:l-DOPA, dihydroxyphenylalanine, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid)/benserazide (2-amino-3-hydroxy-N ′-[(2,3,4-trihydroxyphenyl)methyl]propanehydrazide; PD, Parkinson's disease; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA, 6-hydroxydopamine; prazosin, [4-(4-amino-6,7-dimethoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone; ANOVA, analysis of variance; GBR-12909, 1-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine.
- Received August 5, 2008.
- Accepted October 24, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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