期刊
NEUROPHARMACOLOGY
卷 63, 期 3, 页码 450-459出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2012.04.029
关键词
Alpha6; Dyskinesia; L-dopa; Nicotine; 6-Hydroxydopamine; Parkinson's disease
资金
- National Institute of Health [NS59910, NS65851, DA015663]
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 alpha 6 beta 2* nAChRs, a subtype selectively present in the nigrostriatal pathway, using alpha 6 nAChR subunit null mutant (alpha 6(-/-)) mice. Wildtype and alpha 6(-/-) mice were lesioned by unilateral injection of 6-hydroxydopamine (3 mu g/mu l) into the medial forebrain bundle. They were then given L-dopa (3 mg/kg) plus benserazide (15 mg/kg) 2 -3 wk later. L-dopa-induced AIMs developed to a similar extent in alpha 6(-/-) and wildtype mice. However, AIMs in alpha 6(-/-) mice declined to similar to 50% of that in wildtype mice with continued L-dopa treatment. Nicotine treatment also decreased AIMs by similar to 50% in wildtype mice, although not in alpha 6(-/-) 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 alpha 6(-/-) mice treated with and without nicotine indicate an essential role for alpha 6 beta 2* nAChRs in the maintenance of L-dopa-induced AIMs. These findings suggest that alpha 6 beta 2* nAChR drugs have potential for reducing L-dopa-induced dyskinesias in Parkinson's disease. (C) 2012 Elsevier Ltd. All rights reserved.
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