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来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 该项目评估帕金森病（PD）发展过程中异常运动症状的病理生理学。多巴胺替代在早期阶段具有有益的效果，但长期治疗往往不能完全恢复正常的活动能力，甚至可能产生额外的运动异常。多巴胺反应的改变与调节纹状体神经元活性的多巴胺受体介导机制的变化有关。 然而，其他神经递质系统的变化，如谷氨酸系统也可能发挥作用。 该项目研究了纹状体中改变的多巴胺能传递在左旋多巴异常反应的病理生理学中的作用。该项目的目标是确定纹状体中的药理学靶点，可用于开发帕金森病的长期治疗方法。本研究的目的包括四个方面：（1）研究慢性帕金森病猴纹状体中棘神经元（MSNs）放电改变与多巴胺能亢进的关系。 电生理记录的MSN结合局部纹状体注射特异性谷氨酸受体拮抗剂（2）检查谷氨酸释放产生改变的MSN放电在慢性帕金森病。我们将通过向帕金森病猴的壳核内注入大麻素CB 1作用药物来降低多巴胺能水平，以研究MSN放电变化和运动反应。（3）研究纹状体NMDA受体亚单位基因敲除对多巴胺能慢性治疗的运动反应的影响。 我们将使用病毒载体在啮齿动物中进行siRNA介导的基因沉默，以减少NMDA受体介导的传递并确定其对运动行为的影响（4）研究可在慢性PD中发展并可能与多巴胺能药物的异常运动反应相关的间接纹状体输出驱动。我们将使用多巴胺激动剂在壳核输注，并记录MSN活动和正常和帕金森病猴苍白球外段的神经元。

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. This project evaluates the pathophysiology of abnormal motor symptoms developed in the evolution of Parkinson's disease (PD). Dopamine replacement has beneficial effects in the early stages, but long-term therapy often fails to completely restore normal mobility, and may even produce additional motor abnormalities. Altered dopamine responses have been related to changes of dopamine receptor-mediated mechanisms that regulate the activity of striatal neurons. However, changes in other neurotransmitter systems, such as the glutamate system may also play a role. This project studies the role of altered glutamatergic transmission in the striatum in the pathophysiology of abnormal responses to levodopa. The goal of the project is to identify pharmacologic targets in the striatum that could be used to develop treatments for the long-term therapy of Parkinson's disease. The project comprises four aims: (1) To study the relationship between glutamatergic hyperactivity and altered discharges of striatal medium spiny neurons (MSNs) in chronically parkinsonian monkeys. Electrophysiologic recordings of MSNs are combined with local striatal injections of specific glutamate receptor antagonists (2) To examine the glutamate release to produce altered MSN discharges in chronic parkinsonism. We will reduce glutamatergic levels with cannabinoid CB1-acting drugs infused into the putamen of parkinsonian monkeys to study MSN firing changes and motor responses (3) To investigate the effects of gene knockdown of striatal NMDA receptor subunits on motor responses to chronic dopaminergic treatment. We will use viral vectors for siRNA-mediated gene silencing in rodents to reduce NMDA-receptor mediated transmission and determine its effects on motor behavior (4) To study the indirect striatal output drives that can develop in chronic PD and may be associated with abnormal motor responses to dopaminergic drugs. We will use dopamine agonists in putaminal infusions and record the MSN activity and neurons of the external segment of the globus pallidus in normal and parkinsonian monkeys.