Mechanisms of nicotine-mediated decrease in L-dopa induced-dyskinesias

描述（由申请人提供）：我们的总体目标是阐明L-多巴诱导的运动障碍（LID）的机制，并开发抗运动障碍的策略，重点是烟碱胆碱能系统。左旋多巴治疗是帕金森病治疗的金标准。然而，它的使用与运动异常有关，如运动障碍，可能与疾病本身一样虚弱。很少有治疗LID的方法，可能是因为其发展的机制仍然不确定。虽然广泛的研究涉及许多神经递质，胆碱能系统很少受到关注。这有点令人惊讶，因为纹状体中多巴胺能末梢和胆碱能中间神经元的重叠网络，以及烟碱受体调节纹状体多巴胺释放的众所周知的能力。考虑到这一点，我们假设烟碱胆碱能系统在LIDS中起作用，并开始了将尼古丁和左旋多巴给予帕金森病猴的实验。我们的初步数据表明，尼古丁持续降低帕金森病猴的峰值和总LID（约50%）。此外，随后的一项交叉研究表明，尼古丁治疗也降低了先前给予L-多巴的猴子的LID。左旋多巴的抗帕金森病作用没有下降。我们计划扩展这些新的行为发现，并通过以下具体目标研究尼古丁诱导的LID减少的机制。首先，我们将确定尼古丁给药方案，最有效地减少LID。为了达到这一目的，我们将测试同时和在左旋多巴给药后给予尼古丁的效果，并确定尼古丁诱导的LID下降的剂量和时间依赖性。其次，我们将确定与尼古丁诱导的运动障碍减少相关的烟碱受体亚型。这项工作将为目标3中的研究提供基础，以测试nAChR亚型激动剂的抗运动障碍特性的效果。最后，我们将研究尼古丁减少运动障碍的分子和细胞机制。用尼古丁或选择性尼古丁激动剂治疗代表了减少运动障碍的新方法，并可能导致开发新策略来减轻帕金森病患者左旋多巴治疗的这种使人衰弱的并发症。我们的数据表明，尼古丁给药可减少帕金森病猴中左旋多巴诱导的运动障碍。本提案的目的是评价最佳给药方式，确定烟碱受体亚型，并了解尼古丁发挥其抗运动障碍作用的机制。这些研究有可能为使用靶向烟碱胆碱能系统的药物治疗帕金森病中的运动障碍开辟新的研究方向。

DESCRIPTION (provided by applicant): Our overall aim is to elucidate the mechanisms that underlie L-dopa-induced dyskinesias (LIDs) and to develop anti-dyskinetic strategies, with a focus on the nicotinic cholinergic system. L-dopa therapy is the gold standard for Parkinson's disease treatment. However, its use is associated with movement abnormalities, such as dyskinesias that may be as debilitating as the disease itself. Few treatments are available for LIDs, possibly because the mechanisms responsible for their development are still uncertain. Although extensive studies have implicated numerous neurotransmitters, the cholinergic system has received little attention to date. This is somewhat surprising given the overlapping network of dopaminergic terminals and cholinergic interneurons in the striatum, and the well-known ability of nicotinic receptors to regulate striatal dopamine release. With this in mind, we hypothesized that the nicotinic cholinergic system plays a role in LIDs, and initiated experiments in which nicotine and L-dopa were administered to parkinsonian monkeys. Our preliminary data demonstrate that nicotine consistently reduced peak and total LIDs (~50%) in parkinsonian monkeys. In addition, a crossover study subsequently showed that nicotine treatment also reduced LIDs in monkeys that had previously been given L-dopa. There was no decline in the antiparkinsonian action of L-dopa. We plan to extend these novel behavioral findings, as well as investigate the mechanisms responsible for the nicotine-induced reduction of LIDs through the following specific aims. First, we will identify the nicotine-dosing regimen that most effectively reduces LIDs. To approach this, we will test the effect of nicotine given at the same time and also after L-dopa administration, and determine the dose and time dependency of the nicotine-induced decline in LIDs. Second, we will identify the nicotinic receptor subtypes associated with the nicotine-induced decrease in dyskinesias. This work will provide a basis for the studies in Aim 3 to test the effect of nAChR subtype agonists for their antidyskinetic properties. Lastly, we will study the molecular and cellular mechanisms by which nicotine reduces dyskinesias. Treatment with nicotine, or select nicotinic agonists, represents a novel approach to reduce dyskinesias and could lead to the development of new strategies to attenuate this debilitating complication of L-dopa treatment in patients with Parkinson's disease. PUBLIC HEALTH RELEVANCE Our data show that nicotine administration reduces L-dopa induced dyskinesias in parkinsonian monkeys. The objective of this proposal is to evaluate the optimal mode of administration, to determine the nicotinic receptor subtypes and to understand the mechanisms through which nicotine exerts its antidyskinetic action. These studies have the potential to open up a new research direction for the treatment of dyskinesias in Parkinson's disease using drugs targeted to the nicotinic cholinergic system.