Nicotine Reduces L-DOPA-Induced Dyskinesias by Acting at β2*Nicotinic Receptors
Nicotine Reduces L-DOPA-Induced Dyskinesias by Acting at β2*Nicotinic Receptors
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DOI：
10.1124/jpet.111.182949
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发表时间：
2011-09-01
影响因子：
3.5
通讯作者：
Quik, Maryka
中科院分区：
文献类型：
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作者：
Huang, Luping Z.;Grady, Sharon R.;Quik, Maryka
左旋多巴引起的运动障碍或异常不自主运动 (AIM) 是一种与长期服用左旋多巴治疗帕金森病相关的使人衰弱的不良并发症。目前针对运动障碍的治疗方法很少。我们最近的数据表明，尼古丁可减少帕金森病动物模型中 L-DOPA 诱导的 AIM。一个重要的问题是尼古丁通过其发挥这种有益作用的烟碱乙酰胆碱受体（nAChR）亚型，因为这些知识将有助于开发针对相关受体群体的药物。为了解决这个问题，我们使用了β2nAChR亚基敲除的[β2(-/-)]小鼠，因为含有β2的nAChR是黑质纹状体多巴胺能功能的关键调节因子。通过向右侧内侧前脑束颅内注射 6-羟基多巴胺来损伤所有小鼠。损伤导致β2(-/-) 和野生型小鼠相似程度的黑质纹状体损伤和帕金森病。然后，所有小鼠每天注射一次 L-DOPA (3 mg/kg) 加苄丝肼 (15 mg/kg)，持续 4 周，直至 AIM 完全发育。与野生型小鼠相比，β2(-/-) 小鼠中 L-DOPA 诱导的 AIM 大约减少 40%。有趣的是，尼古丁（300 μg/ml 饮用水）使野生型小鼠 L-DOPA 诱导的 AIM 降低了 40%，但对黑质纹状体部分损伤的 β 2(-/-) 小鼠没有影响。在几乎完全退化的野生型小鼠中，尼古丁介导的 AIM 下降不太明显，这表明多巴胺能末端的突触前 nAChR 具有重大影响。这些数据证明了 β2* nAChR 在尼古丁的抗运动障碍作用中的重要作用，并表明针对这些亚型的药物可能有助于治疗帕金森病中 L-DOPA 引起的运动障碍。
L-DOPA-induced dyskinesias or abnormal involuntary movements (AIMs) are a debilitating adverse complication associated with prolonged L-DOPA administration for Parkinson's disease. Few treatments are currently available for dyskinesias. Our recent data showed that nicotine reduced L-DOPA-induced AIMs in parkinsonian animal models. An important question is the nicotinic acetylcholine receptor (nAChR) subtypes through which nicotine exerts this beneficial effect, because such knowledge would allow for the development of drugs that target the relevant receptor population(s). To address this, we used beta 2 nAChR subunit knockout [beta 2(-/-)] mice because beta 2-containing nAChRs are key regulators of nigrostriatal dopaminergic function. All of the mice were lesioned by intracranial injection of 6-hydroxydopamine into the right medial forebrain bundle. Lesioning resulted in a similar degree of nigrostriatal damage and parkinsonism in beta 2(-/-) and wild-type mice. All of the mice then were injected with L-DOPA (3 mg/kg) plus benserazide (15 mg/kg) once daily for 4 weeks until AIMs were fully developed. L-DOPA-induced AIMs were approximately 40% less in the beta 2(-/-) mice compared with the wild-type mice. It is interesting to note that nicotine (300 mu g/ml in drinking water) reduced L-DOPA-induced AIMs by 40% in wild-type mice but had no effect in beta 2(-/-) mice with partial nigrostriatal damage. The nicotine-mediated decline in AIMs was much less pronounced in wild-type mice with near-complete degeneration, suggesting that presynaptic nAChRs on dopaminergic terminals have a major influence. These data demonstrate an essential role for beta 2* nAChRs in the antidyskinetic effect of nicotine and suggest that drugs targeting these subtypes may be useful for the management of L-DOPA-induced dyskinesias in Parkinson's disease.