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

描述(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(LDS)的机制，并开发抗运动障碍的策略，重点是烟碱型胆碱能系统。L-多巴疗法是帕金森病治疗的金标准。然而，它的使用与运动异常有关，例如运动障碍，可能会像疾病本身一样使人虚弱。目前治疗眼罩的方法很少，可能是因为导致眼睑发炎的机制尚不确定。尽管广泛的研究已经涉及到许多神经递质，但胆碱能系统迄今很少受到关注。考虑到纹状体中多巴胺能终末和胆碱能中间神经元的重叠网络，以及众所周知的尼古丁受体调节纹状体多巴胺释放的能力，这有点令人惊讶。考虑到这一点，我们假设尼古丁胆碱能系统在LIDs中发挥作用，并启动了实验，将尼古丁和L-多巴注射到帕金森病猴子身上。我们的初步数据表明，尼古丁持续减少帕金森病猴的峰值和总LID(~50%)。此外，随后的一项交叉研究表明，尼古丁治疗也减少了之前服用L-多巴的猴子的眼皮。L-多巴的抗帕金森作用没有下降。我们计划扩大这些新的行为发现，并通过以下具体目标调查尼古丁诱导的LIDs减少的机制。首先，我们将确定最有效地减少眼皮的尼古丁剂量方案。为了达到这一目的，我们将测试同时给予尼古丁和在服用L-多巴之后给予尼古丁的效果，并确定尼古丁诱导的眼睑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尼古丁受体亚型。这项工作将为目标3中测试nAChR亚型激动剂抗运动障碍特性的效果的研究提供基础。最后，我们将研究尼古丁减少运动障碍的分子和细胞机制。尼古丁或精选尼古丁激动剂的治疗代表了一种减少运动障碍的新方法，并可能导致开发新的策略来减少L-多巴治疗帕金森病患者的这种令人衰弱的并发症。公共卫生相关性我们的数据显示，尼古丁管理减少L-多巴诱发的帕金森病猴运动障碍。这项建议的目的是评估最佳给药模式，确定尼古丁受体亚型，并了解尼古丁发挥抗运动障碍作用的机制。这些研究有可能为使用针对尼古丁胆碱能系统的药物治疗帕金森病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.