Abstract
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 α2A-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.
Footnotes
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This research was supported by Centre National de la Recherche Scientifique, Université de Provence, Université de la Méditerranée, and Institut de Recherches Internationales Servier.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.109207.
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ABBREVIATIONS: PD, Parkinson's disease; l-DOPA, l-3,4-dihydroxyphenylalanine; DA, dopamine; piribedil, [(methylenedioxy-3,4 benzyl)-4 pyperazinyl-1]-2 pyrimidine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA, 6-hydroxydopamine; RT, reaction time; PLSD, protected least significant difference.
- Received June 8, 2006.
- Accepted August 17, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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