DOPAMINE NEUROTRANSMISSION IN EXPERIMENTAL PARKINSONISM

实验性帕金森症中的多巴胺神经传递

• 批准号: 2038345
• 负责人: PAUL A GARRIS
• 金额: $ 9.12万
• 依托单位: ILLINOIS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-15 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2038345
• 关键词: 6 hydroxydopamine; Parkinson's disease; corpus striatum; denervation; disease /disorder model; dopamine; electrostimulus; extracellular; laboratory rat; microdialysis; neural plasticity; neural transmission; neurotoxicology

DESCRIPTION: The goal of the proposed work is to better understand neuronal compensation in Parkinson's disease. Symptoms of this neurodegenerative disorder are associated with the loss of nigrostriatal dopamine neurons but do not present until deficits are severe. It is postulated that potent adaptive changes in dopamine neurotransmission maintain function during the preclinical or presymptomatic phase. These adaptive mechanisms will be examined in a widely used animal model of Parkinson's disease, the rat with 6-hydroxydopamine lesions. The proposed experiments will study the regulation of extracellular dopamine in the partially denervated striatum, a condition that mimics the preclinical phase. Previous studies using the technique of microdialysis have documented normal concentrations of extracellular dopamine in the lesioned striatum despite losses of up to 80 % of the dopamine terminals. The proposed work will extend these observations by directly investigating the mechanisms responsible for maintaining extracellular dopamine levels. To accomplish this aim, real-time microsensors will be employed to monitor dynamic changes in extracellular dopamine elicited by transient electrical stimulation. In situ rate constants for dopamine release and uptake will be determined from the chemical measurements. Release and uptake are fundamental to dopamine neurotransmission and are the primary determinants of extracellular dopamine concentrations in the brain. A novel hypothesis will be tested. The hypothesis states that normal concentrations of extracellular dopamine are generated in the partially denervated striatum without active compensatory changes in dopamine release and uptake. An understanding of the adaptive changes that maintain dopamine function during the preclinical phase of Parkinson's disease could advance diagnosis and treatment of this disorder as well as provide new insight into other neurodegenerative disease, brain function during the normal aging process and neuronal plasticity.

描述：拟议工作的目标是更好地了解神经元 帕金森病的补偿。 这种神经退行性疾病的症状 这种疾病与黑质纹状体多巴胺神经元的丧失有关， 直到赤字严重时才出现。 据推测， 多巴胺神经传递的适应性变化维持了 临床前或症状前阶段。 这些适应机制将是 在广泛使用的帕金森病动物模型中进行了检查， 6-羟多巴胺损伤 拟议的实验将研究 部分去神经纹状体细胞外多巴胺的调节， 模拟临床前阶段的条件。 以前的研究使用 微透析技术已经记录了正常浓度的 受损纹状体细胞外多巴胺尽管损失高达80% 多巴胺末梢的位置。 拟议的工作将扩大这些意见 通过直接调查负责维护 细胞外多巴胺水平 为了实现这一目标，实时 微传感器将用于监测细胞外的动态变化， 由短暂的电刺激引起的多巴胺。 原地率 多巴胺释放和摄取的常数将由 化学测量。 释放和吸收是多巴胺的基础 是细胞外多巴胺的主要决定因素 大脑中的浓度。 一个新的假设将被测试。 的 一种假说认为，正常浓度的细胞外多巴胺是 产生于部分失神经支配的纹状体， 多巴胺释放和吸收的变化。 对适应性的理解 在临床前阶段维持多巴胺功能的变化 帕金森氏病可以推进这种疾病的诊断和治疗 并为其他神经退行性疾病提供新的见解， 在正常衰老过程中的功能和神经元可塑性。