Regulation of Motor Function in Parkinson's Disease

帕金森病运动功能的调节

• 批准号: 8477310
• 负责人: Stella M Papa
• 金额: $ 33.97万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477310
• 关键词: Agonist; Animals; Area; Basal Ganglia; Behavior; Behavioral; Brain; CNR1 gene; Cannabinoids; Cells; Chronic; Complex; Corpus striatum structure; Development; Disease; Dopamine; Dopamine Agonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopaminergic Agents; Dyskinetic syndrome; Evolution; Excitatory Amino Acid Antagonists; Functional disorder; Globus Pallidus; Glutamate Receptor; Glutamates; Goals; Hyperactive behavior; Infusion procedures; Injection of therapeutic agent; Levodopa; Light; Mediating; Microinjections; Modeling; Molecular; Monkeys; Motor; Motor Activity; Motor Neurons; Movement; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neurons; Neurotransmitters; Outcome; Output; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Plastics; Primates; Regulation; Replacement Therapy; Rodent Model; Role; Signal Transduction; Site; Staging; Substantia nigra structure; Symptoms; System; Technology; Testing; Thalamic structure; Therapeutic; Up-Regulation; advanced disease; dopaminergic neuron; improved; postsynaptic; presynaptic; putamen; receptor; research study; response; tool; transmission process

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.

描述（由申请人提供）：帕金森病（PD）的主要特征是黑质中多巴胺能神经元的丧失，导致基底神经节的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作用，但随着疾病的进展，多巴胺能治疗无法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多巴胺 D1 和 D2 受体介导机制的复杂变化有关，这些机制调节纹状体直接和间接输出。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，其机制可能在帕金森病的慢性演变中发生塑性变化。谷氨酸系统为纹状体提供丰富的皮质和丘脑兴奋性输入，多项证据表明谷氨酸信号的增加可能导致纹状体功能障碍。该项目旨在研究纹状体谷氨酸传递失调在慢性帕金森病多巴胺反应异常的病理生理学中的作用。该项目的最终目标是确定开发帕金森病长期管理新疗法的目标。具体而言，该项目包括三个目标： 1. 研究慢性帕金森猴的谷氨酸能亢进与纹状体投射神经元放电改变之间的关系。我们将使用不同类别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. 研究慢性灵长类帕金森病模型中谷氨酸过量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 作用药物来研究对纹状体神经元和左旋多巴运动反应的影响。 3. 研究慢性灵长类PD模型中纹状体谷氨酸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部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，研究慢性帕金森病纹状体功能障碍的潜在机制，因此可能有助于为因晚期疾病而衰弱的患者开发新疗法。