Regulation of Motor Function in Parkinson's Disease

帕金森病运动功能的调节

• 批准号: 6723869
• 负责人: Stella M Papa
• 金额: $ 34.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6723869
• 关键词: Macaca mulatta; Parkinson' s disease; abnormal involuntary movement; antiparkinson drugs; autoradiography; basal ganglia; behavior test; computer data analysis; denervation; disease /disorder etiology; dopamine; drug adverse effect; electrodes; glutamate receptor; histology; levodopa; neural transmission; neuromuscular disorder; neurons; neurotransmitter antagonist; nonhuman therapy evaluation; pathologic process; receptor binding; receptor sensitivity; single cell analysis

DESCRIPTION (provided by applicant): Motor disturbances of Parkinson's disease are caused by a series of functional alterations in the basal ganglia that derive from dopamine denervation. The mechanisms underlying those functional alterations are not completely understood yet. Moreover, long-term levodopa therapy is usually associated with disabling motor complications, such as motor fluctuations and dyskinesias, whose pathophysiology also remains obscure. The long-term objective of this project is to elucidate the pathophysiologic mechanisms of abnormal motor behaviors in Parkinson's disease in view of developing new and specific therapeutic tools. Thus, this study is aimed: -firstly, to localize functional alterations in specific basal ganglia circuits; -secondly, to determine the glutamate regulation associated to an altered neuronal function; -finally, and based on the foregoing data, to explore new therapeutic approaches by interacting with the glutamatergic neurotransmission in a region-specific manner. Specifically this project comprises three aims: 1. To study the neuronal activity of individual basal ganglia regions by single cell recording in normal and various groups of parkinsonian monkeys (MPTP-treated primates) that exhibit different motor behaviors depending on treatment conditions (i.e.: parkinsonian state, its normalization, and drug-induced dyskinesias). 2. To study the glutamate receptor sensitivity in basal ganglia regions in relation to different motor conditions by comparing the binding of receptors across animal groups. 3. To study the glutamatergic blockade in restricted basal ganglia regions by determining its effects on neuronal activity and motor behavior. The research design includes techniques ranging from single- and multiple single- unit recording of neuronal activity, autoradiographic binding of receptors, to intracerebral administration of drugs in parkinsonian monkeys whose motor abnormalities closely resemble the human disease. This project proposes a novel approach to a comprehensive study of the abnormal motor function in Parkinson's disease. Thus, it will largely contribute to the rationale for new treatments that selectively target particular motor conditions.

描述（由申请人提供）：帕金森氏病的运动障碍是由基底神经节中的一系列功能改变引起的，这些变化源自多巴胺神经胺。这些功能变化的基础机制尚未完全理解。此外，长期左旋多巴疗法通常与残疾运动并发症（如运动波动和动态障碍）有关，其病理生理学也仍然晦涩难懂。该项目的长期目的是阐明帕金森氏病在帕金森氏病中异常运动行为的病理生理机制，以开发新的和特定的治疗工具。因此，这项研究的目的是： - 首先，将功能变化定位在特定的基底神经节电路中； - 第二，确定与神经元功能改变的谷氨酸调节； - 在上述数据上，并基于上述数据，以特定于区域特定的方式与谷氨酸能神经传递相互作用来探索新的治疗方法。具体而言，该项目包括三个目标：1。通过在正常和各种帕金森氏猴（MPTP处理的灵长类动物）中单细胞记录来研究单个基底神经节区域的神经元活动，这些猴子（MPTP处理的灵长类动物）表现出不同的运动行为，这些行为取决于治疗条件（即：帕金森氏症状况（即帕金森氏症），其标准化和药物诱导的Dyskinesias）。 2。研究基底神经节区域中与不同运动条件有关的谷氨酸受体敏感性，通过比较跨动物群体的受体的结合。 3。通过确定其对神经元活性和运动行为的影响，研究受限制的基底神经节区域中的谷氨酸能阻断。研究设计包括神经元活性的单位和多个单位记录，受体自显影结合的技术，到帕金森尼猴子的药物的脑内给药，其运动异常非常类似于人类疾病。该项目提出了一种对帕金森氏病异常运动功能进行全面研究的新颖方法。因此，它将在很大程度上有助于选择性针对特定运动条件的新治疗方法的基本原理。