Nicotine reduces levodopa-induced dyskinesias in lesioned monkeys

Objective: Levodopa, the gold standard for Parkinson's disease treatment, is associated with debilitating abnormal involuntary movements or dyskinesias, for which few treatments are currently available. Studies have implicated numerous neurotransmitters in the development of levodopa-induced dyskinesias. However, the cholinergic system has received little attention despite an extensive overlap between dopaminergic terminals and cholinergic interneurons in the striatum and the well-known ability of nicotine to stimulate striatal dopamine release. Our objective, therefore, was to determine whether nicotine treatment reduced levodopa-induced dyskinesias. Methods: The effect of nicotine (provided in the drinking water) was determined on dyskinesias induced by levodopa (5mg/kg twice daily by oral gavage) in 1-methyl-4-phenyl-1,2,3,6-terrahydropyridine (MPTP) - treated monkeys. Results: Nicotine pretreatment reduced peak and total levodopa-induced dyskinesias in levodopa-naive monkeys over an 8-week period, with a decrease in total dyskinesias of about 50%. A Crossover study was then done in which levodopa-treated monkeys originally receiving vehicle were administered nicotine, whereas the levodopa-treated animals initially receiving nicotine were placed on vehicle. Nicotine treatment to levodopa-primed monkeys led to an approximately 35% reduction in total dyskinesias that lasted for at least 8 weeks, at which time the study was ended. In contrast, a significant increase in levodopa-induced dyskinesias was observed in the group of animals that had previously received nicotine and were then switched to vehicle. Nicotine treatment did not appear to affect the antiparkinsonian action of levodopa. Interpretation: These data suggest that nicotine or selective nicotinic agonists may represent a useful treatment strategy to reduce levodopa-induced dyskinesias.