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BEHAVIORAL PHARMACOLOGY

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

Toronto Western Research Institute, Toronto, Ontario, Canada (N.P.V., S.H.F., T.H.J., J.M.B.); and Institut de Recherches-Servier, Paris, France (M.J.M.)

The mechanisms underlying actions of dihydroxyphenylalanine (L-DOPA) in Parkinson's disease remain to be fully elucidated. Noradrenaline formed from L-DOPA may stimulate ₁-adrenoceptors. We assessed the involvement of 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 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 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. ₁-Adrenoceptors may be involved in pathological responses to L-DOPA treatment, including the dopamine dysregulation syndrome.

Address correspondence to: Naomi Visanji, Division of Brain Imaging and Behavior, Toronto Western Research Institute, 399 Bathurst St., Toronto, ON, Canada. E-mail: naomi.visanji{at}utoronto.ca