Quik_2012_Neuropharmacol_63_450

L-Dopa-induced dyskinesias are a serious side effect that develops in most Parkinson's disease patients on dopamine replacement therapy. Few treatment options are available to manage dyskinesias; however,recent studies show that nicotine reduces these abnormal involuntary movements (AIMs) in parkinsonian animals by acting at nicotinic acetylcholine receptors (nAChRs). Identification of the nAChR subtypes that mediate this reduction in AIMs is important as it will help in the development of nAChR subtype selective drugs for their treatment. Here we investigate the role of alpha6beta2* nAChRs, a subtype selectively present in the nigrostriatal pathway, using a6 nAChR subunit null mutant (alpha6(-)/(-)) mice.Wildtype and alpha6(-)/(-) mice were lesioned by unilateral injection of 6-hydroxydopamine (3 mg/ml) into the medial forebrain bundle. They were then given L-dopa (3 mg/kg) plus benserazide (15 mg/kg) 2e3 wk later. L-dopa-induced AIMs developed to a similar extent in alpha6(-)/(-) and wildtype mice.However, AIMs in alpha6(-)/(-) mice declined to ~50% of that in wildtype mice with continued L-dopa treatment. Nicotine treatment also decreased AIMs by ~50% in wildtype mice, although not in alpha6(-)/(-) mice. There were no effects on parkinsonism under any experimental condition. To conclude, the similar declines in L-dopa-induced AIMs in nicotine-treated wildtype mice and in alpha6(-)/(-) mice treated with and without nicotine indicate an essential role for alpha6beta2* nAChRs in the maintenance of L-dopa-induced AIMs.These findings suggest that alpha6beta2* nAChR drugs have potential for reducing L-dopa-induced dyskinesias in Parkinson's disease.