Role for α6 nicotinic receptors in l-dopa-induced dyskinesias in parkinsonian mice.
Role for α6 nicotinic receptors in l-dopa-induced dyskinesias in parkinsonian mice.
复制标题
α6 烟碱受体在左旋多巴诱导的帕金森小鼠运动障碍中的作用。
DOI：
10.1016/j.neuropharm.2012.04.029
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发表时间：
2012
影响因子：
4.7
通讯作者：
Grady,SharonR
中科院分区：
文献类型：
--
作者：
Quik,Maryka;Park,KeonMin;Hrachova,Maya;Mallela,Archana;Huang,LupingZ;McIntosh,JMichael;Grady,SharonR
左旋多巴引起的运动障碍是一种严重的副作用，在大多数帕金森病患者接受多巴胺替代治疗时都会出现。很少有治疗方案可用于管理运动障碍;然而，最近的研究表明，尼古丁通过作用于烟碱乙酰胆碱受体（nAChR）减少帕金森病动物的这些异常不自主运动（AIM）。鉴定介导AIM减少的nAChR亚型是重要的，因为它将有助于开发用于其治疗的nAChR亚型选择性药物。在这里，我们研究α6β2* nAChR的作用，一个亚型选择性地存在于黑质纹状体通路，使用α6 nAChR亚基无效突变（α6（−/−））小鼠。通过向内侧前脑束单侧注射6-羟基多巴胺（3 μg/μl）对野生型和α6（−/−）小鼠进行损伤。2-3 wk后给予左旋多巴（3 mg/kg）+苄丝肼（15 mg/kg）。左旋多巴诱导的AIM在α6（−/−）和野生型小鼠中的发展程度相似。然而，α6（−/−）小鼠的AIM下降到野生型小鼠持续左旋多巴治疗的50%左右。尼古丁治疗也使野生型小鼠的AIM降低了50%，但在α6（−/−）小鼠中没有。在任何实验条件下，对帕金森症均无影响。总之，尼古丁处理的野生型小鼠和尼古丁处理和未处理的α6（−/−）小鼠中左旋多巴诱导的AIM的相似下降表明α6β2* nAChR在维持左旋多巴诱导的AIM中起着重要作用。这些发现表明，α6β2* nAChR药物具有减少帕金森病中左旋多巴诱导的运动障碍的潜力。
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 α6β2* nAChRs, a subtype selectively present in the nigrostriatal pathway, using α6 nAChR subunit null mutant (α6(−/−)) mice. Wildtype and α6(−/−) mice were lesioned by unilateral injection of 6-hydroxydopamine (3 μg/μl) 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 α6(−/−) and wildtype mice. However, AIMs in α6(−/−) 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 α6(−/−) 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 α6(−/−) mice treated with and without nicotine indicate an essential role for α6β2* nAChRs in the maintenance of l-dopa-induced AIMs. These findings suggest that α6β2* nAChR drugs have potential for reducing l-dopa-induced dyskinesias in Parkinson's disease.