REGULATION OF MOTOR FUNCTION IN PARKINSON'S DISEASE

帕金森病运动功能的调节

• 批准号: 8172345
• 负责人: Stella M Papa
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172345
• 关键词: Behavior; Cannabinoids; Chronic; Computer Retrieval of Information on Scientific Projects Database; Corpus striatum structure; Dopamine; Dopamine Agonists; Dopamine Receptor; Dopaminergic Agents; Evolution; Excitatory Amino Acid Antagonists; Functional disorder; Funding; Gene Silencing; Genes; Globus Pallidus; Glutamates; Goals; Grant; Hyperactive behavior; Infusion procedures; Injection of therapeutic agent; Institution; Levodopa; Mediating; Monkeys; Motor; N-Methyl-D-Aspartate Receptors; Neurons; Neurotransmitters; Output; Parkinson Disease; Parkinsonian Disorders; Pharmaceutical Preparations; Play; Regulation; Research; Research Personnel; Resources; Rodent; Role; Small Interfering RNA; Source; Staging; Symptoms; System; United States National Institutes of Health; Viral Vector; putamen; response; transmission process

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 该项目评估帕金森病 (PD) 演变过程中出现的异常运动症状的病理生理学。多巴胺替代疗法在早期阶段具有有益效果，但长期治疗往往无法完全恢复正常活动能力，甚至可能产生额外的运动异常。多巴胺反应的改变与多巴胺受体介导的调节纹状体神经元活动的机制的变化有关。 然而，其他神经递质系统（例如谷氨酸系统）的变化也可能发挥作用。 该项目研究纹状体中谷氨酸能传递改变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。该项目包括四个目标：（1）研究慢性帕金森猴的谷氨酸能亢进与纹状体中型多棘神经元（MSN）放电改变之间的关系。 MSN 的电生理记录与特定谷氨酸受体拮抗剂的局部纹状体注射相结合 (2) 检查谷氨酸释放在慢性帕金森病中产生改变的 MSN 放电。我们将通过将大麻素 CB1 作用药物注入帕金森猴的壳核来降低谷氨酸水平，以研究 MSN 放电变化和运动反应 (3) 研究纹状体 NMDA 受体亚基的基因敲低对慢性多巴胺能治疗的运动反应的影响。 我们将使用病毒载体在啮齿类动物中进行 siRNA 介导的基因沉默，以减少 NMDA 受体介导的传播并确定其对运动行为的影响 (4) 研究慢性 PD 中可能出现的间接纹状体输出驱动，并可能与异常运动相关对多巴胺能药物的反应。我们将在壳核输注中使用多巴胺激动剂，并记录正常猴和帕金森猴苍白球外节的 MSN 活性和神经元。