Nicotinic receptor-mediated reduction in L-dopa-induced dyskinesias may occur via desensitization

摘要: l-DOPA-induced dyskinesias in Parkinson's disease are a significant clinical problem for which few therapies available. We recently showed that nicotine reduces abnormal involuntary movements (AIMs) parkinsonian animals, suggesting it may be useful the treatment of dyskinesias. The present experiments were performed to understand mechanisms whereby AIMs. used well established model dyskinesias, l-DOPA-treated unilateral 6-hydroxydopamine-lesioned rats. Dose-ranging studies injection 0.1 mg/kg once or twice daily 4 10 days most effectively reduced AIMs, with no worsening parkinsonism. Importantly, single did not reduce indicating nicotine's effect is caused by long-term rather than short-term molecular changes. Administration metabolite cotinine direct nicotine. Experiments nicotinic receptor (nAChR) antagonist mecamylamine done determine whether acted via receptor-mediated mechanism. Unexpectedly, several (1.0 mg/kg) alone significantly ameliorated comparable extent as decline AIMs combined and was additive, exerts its effects nAChR interaction. This latter finding, data showing similar nicotine, both decreased α6β2* increased α4β2* expression, suggests nicotine-mediated improvement involve desensitization block. These have important implications disease.