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; 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目评估了帕金森氏病（PD）发展中异常运动症状的病理生理。多巴胺替代在早期阶段具有有益的作用，但是长期治疗通常无法完全恢复正常的活动能力，甚至可能产生额外的运动异常。多巴胺反应改变与调节纹状体神经元活性的多巴胺受体介导的机制的变化有关。 但是，其他神经递质系统（例如谷氨酸系统）的变化也可能起作用。 该项目研究了谷氨酸能传递改变在纹状体中对左旋多巴异常反应的病理生理学的作用。该项目的目的是确定纹状体中的药理靶标，可用于开发帕金森氏病长期治疗的治疗方法。该项目包括四个目标：（1）研究谷氨酸能多动症与纹状体培养基神经元（MSN）的放电之间的关系。 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（2）相结合，以检查谷氨酸释放，以产生慢性帕金森氏症中MSN放电的改变。我们将使用注入帕金森尼猴子的大麻素CB1作用药物来降低谷氨酸能水平，以研究MSN发射变化和运动反应（3），以研究纹状体NMDA受体亚基基因敲低的影响对慢性多巴胺能治疗的运动反应对运动的影响。 我们将使用病毒矢量进行siRNA介导的啮齿动物中的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），以研究可以在慢性PD中发展的间接纹状体输出驱动器，并且可能与多巴胺疗法药物的异常运动反应有关。我们将使用多巴胺激动剂在priminal输注中，并记录正常猴子和帕金森氏猴的Globus Pallidus外部段的MSN活性和神经元。