Nicotinic receptor agonists decrease L-dopa-induced dyskinesias most effectively in partially lesioned parkinsonian rats.
Nicotinic receptor agonists decrease L-dopa-induced dyskinesias most effectively in partially lesioned parkinsonian rats.
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DOI：
10.1016/j.neuropharm.2010.12.032
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发表时间：
2011-05
影响因子：
4.7
通讯作者：
Quik, Maryka
中科院分区：
文献类型：
--
作者：
Huang, Luping Z.;Campos, Carla;Ly, Jason;Carroll, F. Ivy;Quik, Maryka
左旋多巴治疗帕金森氏症会导致运动障碍或不自主运动异常（AIMs），治疗方法很少。我们之前的数据显示，尼古丁可以降低左旋多巴诱导的帕金森猴和大鼠的AIMs。为了进一步了解尼古丁如何介导其抗运动障碍作用，我们研究了尼古丁受体（nAChR）激动剂对单侧6-羟色胺损伤大鼠纹状体损伤的影响。我们首先在左旋多巴治疗的大鼠身上进行了药物测试，这些大鼠的纹状体多巴胺损伤接近完全（>99%），这是标准的啮齿动物运动障碍模型。与多种nachr相互作用的激动剂Varenicline没有显著降低左旋多巴诱导的AIMs，而选择性作用于α4β2*和α6β2*亚型的5-碘-A-85380 （A-85380）可降低20%的AIMs。相比之下，伐尼克兰和a- 85380均可使左旋多巴诱导的纹状体部分损伤大鼠的AIMs降低40-50%。两种药物都没有恶化左旋多巴的抗帕金森作用。结果表明，选择性尼古丁激动剂可减少运动障碍，并且对纹状体部分多巴胺损伤的动物最有效。这些发现表明突触前多巴胺末端α4β2*和α6β2* nachr对尼古丁的抗运动障碍作用至关重要。目前的数据对于使用尼古丁受体导向药物治疗左旋多巴诱导的运动障碍具有重要意义，运动障碍是帕金森病多巴胺替代疗法的一种衰弱的运动并发症。
L-dopa therapy for Parkinson's disease leads to dyskinesias or abnormal involuntary movement (AIMs) for which there are few treatment options. Our previous data showed that nicotine administration reduced L-dopa-induced AIMs in parkinsonian monkeys and rats. To further understand how nicotine mediates its antidyskinetic action, we investigated the effect of nicotinic receptor (nAChR) agonists in unilateral 6-OHDA-lesioned rats with varying striatal damage. We first tested the drugs in L-dopa-treated rats with a near-complete striatal dopamine lesion (>99%), the standard rodent dyskinesia model. Varenicline, an agonist that interacts with multiple nAChRs, did not significantly reduce L-dopa-induced AIMs, while 5-iodo-A-85380 (A-85380), which acts selectively at α4β2* and α6β2* subtypes, reduced AIMs by 20%. By contrast, both varenicline and A-85380 reduced L-dopa-induced AIMs by 40–50% in rats with a partial striatal dopamine lesion. Neither drug worsened the antiparkinsonian action of L-dopa. The results show that selective nicotinic agonists reduce dyskinesias, and that they are optimally effective in animals with partial striatal dopamine damage. These findings suggest that presynaptic dopamine terminal α4β2* and α6β2* nAChRs are critical for nicotine’s antidyskinetic action. The current data have important implications for the use of nicotinic receptor-directed drugs for L-dopa-induced dyskinesias, a debilitating motor complication of dopamine replacement therapy for Parkinson’s disease.
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