EVIDENCE FOR A ROLE FOR α6*nAChRs IN L-DOPA-INDUCED DYSKINESIAS USING PARKINSONIAN α6*nAChR GAIN-OF-FUNCTION MICE

L-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson's disease. The mechanisms that underlie LIDs are currently unclear. However, preclinical studies indicate that nicotinic acetylcholine receptors (nAChRs) play a role, suggesting that drugs targeting these receptors may be of therapeutic benefit. To further understand the involvement of alpha 6 beta 2* nAChRs in LIDs, we used gain-of-function alpha 6* nAChR (alpha 6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and alpha 6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3 mu g/ml) into the medial forebrain bundle. Three to 4 wk later, they were administered L-dopa (3 mg/kg) plus benserazide (15 mg/kg) until stably dyskinetic. L-dopa-induced abnormal involuntary movements (AIMs) were similar in alpha 6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300 mu g/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in alpha 6L9S mice at a maximally tolerated nicotine dose of 20 mu g/ml. However, the nAChR antagonist mecamylamine (1 mg/kg ip 30 min before L-dopa) reduced L-dopa-induced AIMs in both alpha 6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in alpha 6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive alpha 6 beta 2* nAChRs may desensitize less readily. The present data show that alpha 6 beta 2* nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.