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

尼古丁介导的减少左旋多巴诱发的运动障碍的机制

• 批准号: 7573327
• 负责人: MARYKA QUIK
• 金额: $ 68.52万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7573327
• 关键词: Adverse effects; Agonist; Antiparkinson Agents; Attention; Attenuated; Behavioral; Biological Assay; Complex; Complication; Corpus striatum structure; Coupling; Cross-Over Studies; Cyclin-Dependent Kinase 5; Data; Dependency; Development; Disease; Dopamine; Dopamine Receptor; Dose; Drug Delivery Systems; Dyskinetic syndrome; Future; GTP-Binding Proteins; Goals; Gold; Interneurons; Knowledge; L-DOPA induced dyskinesia; Lead; Levodopa; Link; MPTP Poisoning; Mediating; Metabolism; Mind; Molecular; Monkeys; Movement; Neurotransmitters; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Opioid Receptor; Parkinson Disease; Parkinsonian Disorders; Patients; Pharmaceutical Preparations; Play; Property; Regulation; Research; Role; Site; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Treatment Protocols; Work; base; cholinergic; drug testing; insight; nigrostriatal pathway; novel; novel strategies; postsynaptic; presynaptic; public health relevance; receptor; receptor expression; research study; treatment strategy

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.

描述（由申请人提供）：我们的总体目的是阐明L-DOPA引起的运动障碍（LID）的机制并开发抗疾病策略，重点是烟碱胆碱能系统。 L-DOPA疗法是帕金森氏病治疗的黄金标准。但是，它的使用与运动异常有关，例如疾病本身就像疾病本身一样令人衰弱的运动障碍。很少有用于盖子的治疗方法，可能是因为导致其发展的机制仍然不确定。尽管广泛的研究暗示了许多神经递质，但迄今为止，胆碱能系统几乎没有受到关注。考虑到纹状体中多巴胺能末端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能力，这有点令人惊讶。考虑到这一点，我们假设烟碱胆碱能系统在盖子中起作用，并开始实验，其中将尼古丁和L-DOPA用于帕金森尼猴子。我们的初步数据表明，尼古丁始终降低帕金森猴的峰值和总盖子（约50％）。此外，一项跨界研究随后表明，尼古丁治疗还降低了以前给出L-DOPA的猴子的盖子。 L-DOPA的反帕金森氏症行动没有下降。我们计划扩展这些新颖的行为发现，并研究通过以下特定目的通过以下特定目的来减少尼古丁引起的盖子的机制。首先，我们将确定最有效地降低盖子的尼古丁剂量方案。为了解决这个问题，我们将同时测试尼古丁的作用，并在L-DOPA给药后测试，并确定尼古丁诱导的盖子下降的剂量和时间依赖性。其次，我们将确定与尼古丁引起的运动障碍降低相关的烟碱受体亚型。这项工作将为AIM 3的研究提供基础，以测试NACHR亚型激动剂对抗肌间术特性的影响。最后，我们将研究尼古丁降低运动障碍的分子和细胞机制。尼古丁或选择烟碱激动剂的治疗是一种减少运动障碍的新方法，并可能导致新策略的发展，以减轻帕金森氏病患者L-DOPA治疗的这种使人衰弱的并发症。公共卫生相关性我们的数据表明，尼古丁管理会减少L-DOPA诱发的帕金森尼猴子的运动障碍。该建议的目的是评估最佳给药方式，确定烟碱受体亚型，并了解尼古丁施加其抗体运动作用的机制。这些研究有可能使用针对烟素胆碱能系统的药物为帕金森氏病治疗帕金森氏病的新研究方向。