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缺失，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具有有益的效果，但随着疾病的进展，多巴胺能治疗不能恢复正常的活动性，甚至产生额外的运动异常。这种对多巴胺的反应改变与多巴胺D1和D2受体介导的调节纹状体直接和间接输出的机制的复杂变化有关。然而，纹状体投射神经元的活动也受到其他神经递质系统的调节，其机制可能在PD的慢性演变中发生可塑性变化。谷氨酸系统向纹状体提供丰富的皮层和丘脑兴奋性输入，并且几条证据表明谷氨酸能信号的增加可能有助于纹状体功能障碍。本项目旨在研究纹状体多巴胺能传递失调在慢性PD患者异常多巴胺反应的病理生理学中的作用。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。研究慢性帕金森病猴纹状体投射神经元放电改变与多巴胺能兴奋的关系。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.研究慢性灵长类PD模型中过量谷氨酸释放在纹状体放电改变机制中的作用。我们将在纹状体注射或输注中使用大麻素CB1作用药物，以研究对纹状体神经元和左旋多巴运动反应的影响。3.在慢性灵长类PD模型中，研究纹状体多巴胺能亢进对间接纹状体输出通路驱动的多巴胺反应变化的作用。我们将在纹状体输注中使用谷氨酸拮抗剂来检查外苍白球神经元对选择性多巴胺激动剂的反应。 该项目结合了药理学和电生理学领域的现代技术，研究慢性PD中纹状体功能障碍的潜在机制，因此，它可能有助于为晚期疾病衰弱的患者开发新的治疗方法。

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.