REGULATION OF MOTOR FUNCTION IN PARKINSON'S DISEASE

帕金森病运动功能的调节

• 批准号: 8357414
• 负责人: Stella M Papa
• 金额: $ 4.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357414
• 关键词: Cannabinoids; Chronic; Corpus striatum structure; Dopamine; Dopamine Receptor; Dopaminergic Agents; Evolution; Excitatory Amino Acid Antagonists; Functional disorder; Funding; Globus Pallidus; Glutamates; Goals; Grant; Hyperactive behavior; Infusion procedures; Injection of therapeutic agent; Levodopa; Mediating; Monkeys; Motor; National Center for Research Resources; Neurons; Neurotransmitters; Output; Parkinson Disease; Parkinsonian Disorders; Pharmaceutical Preparations; Play; Primates; Principal Investigator; Regulation; Research; Research Infrastructure; Resources; Role; Source; Staging; Symptoms; System; United States National Institutes of Health; base; cost; putamen; response; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 in dopamine receptor-mediated mechanisms regulating the activity of striatal neurons. However, changes in other neurotransmitter systems may also play a role. Based on our previous studies in this project, we focus our continuation studies on the role of striatal glutamatergic transmission in the pathophysiology of abnormal responses to levodopa. The goal of these studies is to identify pharmacologic targets that could serve to develop new treatments for the long-term therapy of PD. The project comprises four aims: (1) To study the relationship between glutamatergic hyperactivity and altered discharges of striatal medium spiny neurons (MSNs) in parkinsonian monkeys. Electrophysiologic recordings of MSNs are combined with striatal injections of specific glutamate receptor antagonists. (2) To examine whether increased glutamate release is involved in the altered MSN discharges. We will reduce glutamatergic levels with cannabinoid CB1-acting drugs infused into the putamen of parkinsonian monkeys to study MSN firing changes and levodopa motor responses. (3) To study the changes in indirect striatal outputs that develop in chronic PD and are associated with abnormal responses to dopaminergic drugs. We will use glutamate antagonists in putaminal infusions and record the neuronal activity of the external segment of the globus pallidus in normal and parkinsonian monkeys.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 该项目评估帕金森病（PD）发展过程中异常运动症状的病理生理学。多巴胺替代在早期阶段具有有益的效果，但长期治疗往往不能完全恢复正常的活动能力，甚至可能产生额外的运动异常。多巴胺反应的改变与调节纹状体神经元活性的多巴胺受体介导机制的变化有关。 然而，其他神经递质系统的变化也可能发挥作用。基于我们以前在这个项目中的研究，我们集中我们的继续研究的作用，纹状体多巴胺能传递的异常反应的病理生理学左旋多巴。这些研究的目的是确定药理学靶点，可用于开发PD长期治疗的新疗法。本研究的目的包括四个方面：（1）研究帕金森病猴纹状体中棘神经元（MSNs）放电改变与多巴胺能亢进的关系。 MSN的电生理记录与特定谷氨酸受体拮抗剂的纹状体注射相结合。(2)目的：研究谷氨酸释放的增加是否与MSN放电的改变有关。我们将通过将大麻素CB 1作用药物注入帕金森病猴的壳核来降低神经元兴奋性水平，以研究MSN放电变化和左旋多巴运动反应。(3)研究慢性PD患者纹状体间接输出的变化，并与多巴胺能药物的异常反应有关。我们将使用谷氨酸拮抗剂在壳核输注，并记录正常和帕金森病猴的苍白球外段的神经元活动。