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）：帕金森氏病（PD）的特征主要是底底尼格拉（Nigra）中多巴胺能神经元的丧失，导致基底神经节和典型运动症状的功能改变。多巴胺替代疗法在早期阶段具有有益的作用，但是随着疾病的进展，多巴胺能疗法无法恢复正常的迁移率，甚至会产生额外的运动异常。这种对多巴胺的反应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性也受其他神经递质系统的调节，这些神经递质系统的机制可能会在PD的慢性进化中发生塑性变化。谷氨酸系统为纹状体提供丰富的皮质和丘脑兴奋性输入，几条证据表明，谷氨酸能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能传播失调在慢性PD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为PD长期管理开发新治疗方法的目标。该项目特别包括三个目的：1。研究谷氨酸能多动症与变化帕金森尼猴子纹状体投射神经元的放电之间的关系。我们将使用不同类别的谷氨酸拮抗剂来阻止局部用药物注射到大脑的纹状体受体。 2。检验过度谷氨酸释放在PD慢性灵长类动物模型中纹状体放电机制中的贡献。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的影响以及对左旋多巴的运动反应。 3。研究纹状体谷氨酸能多动症对在PD的慢性灵长类动物模型中间接纹状体输出途径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中选择性多巴胺激动剂的反应。 该项目结合了药理和电生理区域中的现代技术，以研究慢性PD中纹状体功能障碍的潜在机制，因此，它可能有助于开发因晚期疾病衰老的患者而开发的新疗法。