Regulation of Motor Function in Parkinson's Disease

描述（由申请人提供）：帕金森病的运动障碍是由多巴胺去神经支配引起的基底神经节的一系列功能改变引起的。这些功能改变背后的机制尚未完全了解。此外，长期左旋多巴治疗通常与致残性运动并发症有关，如运动波动和运动障碍，其病理生理学也仍然不清楚。本项目的长期目标是阐明帕金森氏病运动行为异常的病理生理机制，以开发新的特异性治疗工具。因此，本研究旨在：- 首先，定位特定基底神经节回路中的功能改变; -其次，确定与改变的神经元功能相关的谷氨酸调节; -最后，基于上述数据，通过以区域特异性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。通过单细胞记录研究正常和各组帕金森病猴（MPTP治疗的灵长类动物）中单个基底神经节区域的神经元活动，这些猴根据治疗条件表现出不同的运动行为（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受体的结合，研究基底神经节区域与不同运动条件相关的谷氨酸受体敏感性。3.研究限制性基底节区多巴胺能阻滞对神经元活动和运动行为的影响。研究设计包括从单个和多个单个单位记录神经元活动、受体放射自显影结合到帕金森病猴脑内给药的技术，帕金森病猴的运动异常与人类疾病非常相似。该项目提出了一种新的方法来全面研究帕金森病的运动功能异常。因此，它将在很大程度上有助于选择性地针对特定运动条件的新治疗的理论基础。

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.