Regulation of Motor Function in Parkinson's Disease

描述（由申请人提供）：帕金森病（PD）的主要特征是黑质多巴胺能神经元的丧失，导致基底神经节功能改变和典型的运动症状。多巴胺替代疗法在早期阶段有有益的效果，但随着疾病的进展，多巴胺能治疗不能恢复正常的活动能力，甚至产生额外的运动异常。这种对多巴胺反应的改变与调节纹状体直接和间接输出的多巴胺D1和D2受体介导的机制的复杂变化有关。然而，纹状体投射神经元的活动还受到其他神经递质系统的调控，其机制可能在PD的慢性演变过程中发生可塑性变化。谷氨酸系统为纹状体提供了丰富的皮层和丘脑兴奋输入，一些证据表明，谷氨酸信号的增加可能导致纹状体功能障碍。本项目旨在研究纹状体谷氨酸能传递异常在慢性帕金森病患者多巴胺异常反应病理生理中的作用。该项目的最终目标是确定开发PD长期管理新疗法的目标。具体而言，该项目包括三个目标：1。研究慢性帕金森猴谷氨酸能亢进与纹状体投射神经元放电改变的关系。我们将使用不同种类的谷氨酸拮抗剂，通过向大脑注射药物来局部阻断纹状体受体。2. 目的探讨慢性帕金森病灵长类动物纹状体放电改变机制中谷氨酸过量释放的作用。我们将在纹状体注射或输注大麻素cb1作用药物来研究左旋多巴对纹状体神经元和运动反应的影响。3. 研究慢性帕金森病灵长类动物纹状体谷氨酸能亢进在纹状体间接输出通路驱动的多巴胺反应变化中的作用。我们将使用谷氨酸拮抗剂在纹状体输注，以检查选择性多巴胺激动剂在外苍白质神经元的反应。本项目结合现代药理学和电生理技术，研究慢性帕金森病纹状体功能障碍的潜在机制，为晚期帕金森病患者开发新的治疗方法提供参考。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is characterized primarily by the loss of dopaminergic neurons in the substantia nigra that causes functional alterations of basal ganglia and typical motor symptoms. Dopamine replacement therapy has beneficial effects in the early stages, but as disease progresses, dopaminergic treatments fail to restore normal mobility and even produce additional motor abnormalities. Such altered responses to dopamine have been related to complex changes of dopamine D1 and D2 receptor-mediated mechanisms that regulate the striatal direct and indirect outputs. However, the activity of striatal projection neurons is also regulated by other neurotransmitter systems whose mechanisms may undergo plastic changes in the chronic evolution of PD. The glutamate system provides abundant cortical and thalamic excitatory inputs to the striatum, and several lines of evidence indicate that the increase of glutamatergic signaling may contribute to striatal dysfunction. This project is intended to study the role of dysregulation of striatal glutamatergic transmission in the pathophysiology of abnormal dopamine responses in chronic PD. The ultimate goal of the project is to identify targets for developing new treatments for the long-term management of PD. Specifically the project comprises three aims: 1. to study the relationship between glutamatergic hyperactivity and altered discharges of striatal projection neurons in chronically parkinsonian monkeys. We will use different classes of glutamate antagonists to block the striatal receptors locally with drug injections into the brain. 2. To examine the contribution of excessive glutamate release in the mechanisms of altered striatal discharges in the chronic primate model of PD. We will use cannabinoid CB1-acting drugs in striatal injections or infusions to study the effects on striatal neurons and motor responses to levodopa. 3. To study the role of striatal glutamatergic hyperactivity on changes in dopamine responses driven by the indirect striatal output pathway in the chronic primate model of PD. We will use glutamate antagonists in striatal infusions to examine the responses to selective dopamine agonists in external pallidal neurons. The project combines modern technologies in pharmacological and electrophysiological areas to study the underlying mechanisms of striatal dysfunction in chronic PD, and thus, it may contribute to developing new therapies for patients debilitated by the advanced disease.