Regulation of Motor Function in Parkinson's Disease

描述(申请人提供)：帕金森氏病的运动障碍是由多巴胺失神经引起的一系列基底神经节功能改变引起的。这些功能改变背后的机制还没有完全弄清楚。此外，长期的左旋多巴治疗通常与致残运动并发症有关，如运动波动和运动障碍，其病理生理也仍不清楚。本项目的长期目标是从开发新的、特异的治疗手段的角度，阐明帕金森病患者异常运动行为的病理生理机制。因此，本研究的目的是：-首先，定位特定基底节回路的功能改变；-其次，确定与神经元功能改变相关的谷氨酸调节；-最后，基于上述数据，通过以区域特异性的方式与谷氨酸能神经传递相互作用，探索新的治疗方法。具体地说，本项目包括三个目标：1.通过单细胞记录研究正常和不同组帕金森病猴(MPTP治疗的灵长类动物)的单个基底节区域的神经元活动，这些组表现出不同的运动行为，取决于治疗条件(即：帕金森状态、其正常化和药物诱导的运动障碍)。2.通过比较不同动物组间谷氨酸受体的结合情况，研究不同运动条件下基底节区谷氨酸受体的敏感性。3.通过测定谷氨酸能阻滞对神经元活动和运动行为的影响，研究谷氨酸能阻滞对基底节区的影响。这项研究设计包括各种技术，从单个和多个单位记录神经元活动，受体的放射自显影结合，到帕金森病猴子的脑内给药，这些猴子的运动异常与人类疾病非常相似。这个项目提出了一种新的方法来全面研究帕金森病患者的运动功能异常。因此，这将在很大程度上有助于有选择地针对特定运动状况的新治疗方法的理论基础。

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.