The dopamine agonist Piribedil with L-DOPA improves attentional dysfunction: Relevance for Parkinson's disease

Cognitive deficits are often associated with motor symptoms in Parkinson's disease. This study investigates the ability of piribedil ([(methylenedioxy-3,4benzyl)-4pyperazinyl-1]-2 pyrimidine), a D-2/D-3 dopamine (DA) receptor agonist with antagonist activity at alpha(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.