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

Cognitive deficits are often associated with motor symptoms in Parkinson9s disease. This study investigates the ability of piribedil ([(methylenedioxy-3,4 benzyl)-4 pyperazinyl-1]-2 pyrimidine), a D 2 /D 3 dopamine (DA) receptor agonist with antagonist activity at α 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 Parkinson9s disease might improve cognitive functions while reducing the risk for motor complications.