Role for 伪6 nicotinic receptors in l-dopa-induced dyskinesias in parkinsonian mice

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• 作者：Maryka Quik^a ; ^{maryka.quik@sri.com} ; Keon Min Park^a ; Maya Hrachova^a ; Archana Mallela^a ; Luping Z. Huang^a ; J. Michael McIntosh^b ; ^c ; Sharon R. Grady^d
• 关键词：Alpha6 ; Dyskinesia ; l-dopa ; Nicotine ; 6-Hydroxydopamine ; Parkinson's disease
• 刊名：Neuropharmacology
• 出版年：2012
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：September, 2012
• 卷：63
• 期：3
• 页码：450-459
• 文件大小：450 K

摘要

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 伪6尾2* nAChRs, a subtype selectively present in the nigrostriatal pathway, using 伪6 nAChR subunit null mutant (伪6(鈭?鈭?) mice. Wildtype and 伪6(鈭?鈭? mice were lesioned by unilateral injection of 6-hydroxydopamine (3聽渭g/渭l) into the medial forebrain bundle. They were then given l-dopa (3聽mg/kg) plus benserazide (15聽mg/kg) 2-3聽wk later. l-dopa-induced AIMs developed to a similar extent in 伪6(鈭?鈭? and wildtype mice. However, AIMs in 伪6(鈭?鈭? mice declined to 鈭?0%of that in wildtype mice with continued l-dopa treatment. Nicotine treatment also decreased AIMs by 鈭?0%in wildtype mice, although not in 伪6(鈭?鈭? 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 伪6(鈭?鈭? mice treated with and without nicotine indicate an essential role for 伪6尾2* nAChRs in the maintenance of l-dopa-induced AIMs. These findings suggest that 伪6尾2* nAChR drugs have potential for reducing l-dopa-induced dyskinesias in Parkinson's disease.