TY - JOUR T1 - Nicotinic Receptor-Mediated Reduction in <span class="sc">l</span>-DOPA-Induced Dyskinesias May Occur via Desensitization JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 929 LP - 938 DO - 10.1124/jpet.109.162396 VL - 333 IS - 3 AU - Tanuja Bordia AU - Carla Campos AU - J. Michael McIntosh AU - Maryka Quik Y1 - 2010/06/01 UR - http://jpet.aspetjournals.org/content/333/3/929.abstract N2 - l-DOPA-induced dyskinesias in Parkinson's disease are a significant clinical problem for which few therapies are available. We recently showed that nicotine reduces l-DOPA-induced abnormal involuntary movements (AIMs) in parkinsonian animals, suggesting it may be useful for the treatment of l-DOPA-induced dyskinesias. The present experiments were performed to understand the mechanisms whereby nicotine reduces l-DOPA-induced AIMs. We used a well established model of dyskinesias, l-DOPA-treated unilateral 6-hydroxydopamine-lesioned rats. Dose-ranging studies showed that injection of 0.1 mg/kg nicotine once or twice daily for 4 or 10 days most effectively reduced AIMs, with no worsening of parkinsonism. Importantly, a single nicotine injection did not reduce AIMs, indicating that nicotine's effect is caused by long-term rather than short-term molecular changes. Administration of the metabolite cotinine did not reduce AIMs, suggesting a direct effect of nicotine. Experiments with the nicotinic receptor (nAChR) antagonist mecamylamine were done to determine whether nicotine acted via a receptor-mediated mechanism. Unexpectedly, several days of mecamylamine injection (1.0 mg/kg) alone significantly ameliorated dyskinesias to a comparable extent as nicotine. The decline in AIMs with combined nicotine and mecamylamine treatment was not additive, suggesting that nicotine exerts its effects via a nAChR interaction. This latter finding, combined with data showing that mecamylamine reduced AIMs to a similar extent as nicotine, and that nicotine or mecamylamine treatment both decreased α6β2* and increased α4β2* nAChR expression, suggests that the nicotine-mediated improvement in l-DOPA-induced AIMs may involve a desensitization block. These data have important implications for the treatment of l-DOPA-induced dyskinesias in Parkinson's disease. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -