α1-Adrenoceptors Mediate Dihydroxyphenylalanine-Induced Activity in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Macaques

The mechanisms underlying actions of dihydroxyphenylalanine ( l -DOPA) in Parkinson's disease remain to be fully elucidated. Noradrenaline formed from l -DOPA may stimulate α 1 -adrenoceptors. We assessed the involvement of α 1 -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 α 1 -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 α 1 -adrenoceptors plays no major role in the antiparkinsonian and dyskinetic effects of l -DOPA per se, it does contribute to the induction of hyperactivity. α 1 -Adrenoceptors may be involved in pathological responses to l -DOPA treatment, including the dopamine dysregulation syndrome.