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BEHAVIORAL PHARMACOLOGY

The Dopamine Agonist Piribedil with L-DOPA Improves Attentional Dysfunction: Relevance for Parkinson's Disease

Laboratoire de Neurobiologie de la Cognition Unité Mixte de Recherche 6155, Centre National de la Recherche Scientifique-Université de Provence, Marseille, France (N.T.-L., B.M., C.P., C.B., M.A.); Institut de Biologie du Développement de Marseille-Luminy, Unité Mixte de Recherche 6216, Centre National de la Recherche Scientifique-Université de la Méditerranée, Marseille, France (A.N.); and Institut de Recherches Internationales Servier, Courbevoie, France (C.C., P.M.)

Cognitive deficits are often associated with motor symptoms in Parkinson's disease. This study investigates the ability of piribedil ([(methylenedioxy-3,4 benzyl)-4 pyperazinyl-1]-2 pyrimidine), a D₂/D₃ dopamine (DA) receptor agonist with antagonist activity at _2A-adrenoceptors, to restore motor and attentional deficits in nigrostriatal 6-hydroxydopamine-lesioned rats. Subjects were trained to depress a lever, detect a stimulus occurring after variable foreperiods, and release the lever quickly afterward. Striatal DA depletions produce deficits in the timing of foreperiods and prolong reaction times. Although a subchronic treatment with piribedil (0.1–2 mg/kg) is not effective, a dose of 0.3 mg/kg administered for 3 weeks significantly reverses the akinetic deficits produced by the striatal dopamine depletion and progressively improves attentional deficits. When coadministered with the dopamine prodrug L-3,4-dihydroxyphenylalanine (L-DOPA) (3 mg/kg), piribedil (0.3 mg/kg) promotes a rapid and full recovery of preoperative performance. These results suggest that administration of L-DOPA in combination with piribedil in a chronic treatment as either initial or supplemental therapy for Parkinson's disease might improve cognitive functions while reducing the risk for motor complications.

Address correspondence to: Dr. Marianne Amalric, Laboratoire de Neurobiologie de la Cognition, UMR 6155 Centre National de la Recherche Scientifique-Université de Provence, Case C, 3 Place Victor Hugo, 13331 Marseille cedex 3, France. E-mail: marianne.amalric{at}up.univ-mrs.fr

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