REGULATION OF MOTOR FUNCTION IN PARKINSON'S DISEASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究旨在探讨帕金森氏病（PD）行为异常的病理生理学机制，以期开发新的治疗手段。 该项目的一个中心的具体目标是表征基底神经节功能的改变所示的区域神经元活动的变化。 本项目在这方面取得了很大的进展，在过去的一段时间里，我们分析了大部分来自纹状体和苍白球（GPe）外段的单细胞记录的电生理数据。在外部苍白球，放电率与纹状体神经元活动的结果一致。 我们的研究结果开始揭示慢性帕金森综合征导致的基底神经节的重要功能变化，这些变化对帕金森病的经典模型进行了根本性的修改。在过去的一年中，我们还发现了纹状体神经元活动模式的显着改变，这些变化与特定的运动行为（如左旋多巴诱导的运动障碍）密切相关。 这些发现为帕金森病运动行为异常的发病机制提供了重要信息，并引导我们根据生理学发现提出新的治疗假设。我们的研究已经假设，作用于大麻素系统的药物可能对帕金森病症状产生影响，因为大麻素CB 1受体介导的对纹状体中谷氨酸释放的影响似乎在慢性帕金森病状态下高度增强。 我们目前正在测试特定的大麻能药物对慢性帕金森病猴子纹状体的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this project has been to elucidate the pathophysiologic mechanisms of abnormal behaviors in Parkinson's disease (PD) in view of developing new therapeutic tools. A central specific aim of the project is to characterize basal ganglia functional alterations as shown by changes of regional neuronal activity. This project has made great progress in this specific aim, and during the last period we have analyzed most electrophysiology data of single cell recording from the striatum and the external segment of the globus pallidus (GPe). In the external pallidum, firing rates are congruent with findings of neuronal activity in the striatum. Our results are starting to unveil important functional changes in basal ganglia as a result of chronic parkinsonism that pose radical revisions of the classic models of Parkinson's disease. During the past year, we have also found significant alterations in the pattern of striatal neuronal activity that correlate well with specific motor behaviors such as levodopa-induced dyskinesias. These findings contribute critical information to the pathogenesis of abnormal motor behaviors in PD, and lead us to new therapeutic hypotheses based on our physiology findings. Our studies have posited that drugs acting on the cannabinoid system may have an impact on parkinsonian symptoms because of the cannabinoid CB1 receptor-mediated effects upon the glutamate release in the striatum that appears to be highly augmented in the chronic parkinsonian state. We are currently testing the striatal effects of specific cannabinergic agents in chronic parkinsonian monkeys.