Dopamine Neurotransmission in Experimental Parkinsonism

实验性帕金森症中的多巴胺神经传递

• 批准号: 6505364
• 负责人: PAUL A GARRIS
• 金额: $ 11.76万
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6505364
• 关键词: 6 hydroxydopamine; Parkinson's disease; corpus striatum; denervation; disease /disorder model; dopamine; electrochemistry; electrophysiology; electrostimulus; extracellular; laboratory rat; microelectrodes; neural plasticity; neural transmission; neurons; neurotoxicology; neurotransmitter biosynthesis; neurotransmitter metabolism; substantia nigra; tissue /cell culture; wakefulness

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a devastating neuropathology that afflicts nearly one million people in the United States along and millions more worldwide. The classic triad of symptoms, resting tremor, rigidity and akinesia, typically occur in the fifth and sixth decade of life. Interestingly, although PD is clearly associated with degeneration of nigrostriatal dopamine (DA) neurons in the brain, symptoms do not present until the loss of striatal DA is nearly complete (>80 percent). In fact lesions of greater than 90 percent are required before the symptoms become marked. The maintenance of normal motor function despite extensive neurodegeneration suggests the existence of potent compensatory mechanisms. Early in this study of PD, Hornykiewicz and co-workers coined "adaptive capacity" to describe this phenomenon. Later work, relying on animal models, demonstrated that extracellular DA is maintained at normal levels in the striatum until the lesion exceeds approximately 80 percent. Zigmond and co-workers have developed what appeared to be for several years a convincing hypothesis for compensation: diffusion of DA from intact into depleted regions and an adaptive increase in DA release and synthesis preserve a functional dopaminergic tone. More recent results have challenged the postulated roles played by DA release, uptake and synthesis in this model. Because a coherent picture has yet to emerge from the conflicting results however, there is a great need to establish how DA signaling is preserved in the striatum following partial denervation. The overall goal of the proposed project is to investigate compensatory adaptation in nigrostriatal DA neurons during the preclinical or asymptomatic phase of PD. To this end, the regulation of extracellular DA will be characterized in the 6-hydroxydopamine-lesioned rat, a widely used animal model of this pathology. Real-time microsensors with millisecond temporal and micron spatial resolution will monitor extracellular DA dynamics elicited by transient electrical stimulation. There are two specific aims. The first aim is to evaluate extracellular DA evoked by a physiological frequency, and the DA release and uptake rates that support these levels, in the awake animal using new technology developed by the P.I. These experiments will extend his previous analysis in the anesthetized animal. The second aim is to determine the relationship between DA release and synthesis in vivo. Although a compensatory change in DA synthesis is perhaps the best established adaptation, its relationship to DA release in the denervated striatum is currently debated. Taken together, the proposed experiments will yield new insight into how a functional dopaminergic tone is maintained in the striatum despite the extensive loss of DA neurons.

描述(申请人提供)：帕金森氏病(PD)是一种毁灭性的神经病理，困扰着美国近100万人和全球数百万人。典型的三联体症状，静止性震颤、僵硬和动作迟缓，通常发生在生命的第五和第六个十年。有趣的是，尽管帕金森病显然与大脑中黑质纹状体多巴胺(DA)神经元的退化有关，但直到纹状体DA的丧失接近完全时才会出现症状(&gt；80%)。事实上，在症状变得明显之前，需要90%以上的损害。尽管有广泛的神经变性，但仍能维持正常的运动功能，这表明存在有效的代偿机制。在这项关于帕金森病的早期研究中，Hornykiewicz和他的同事创造了“适应能力”来描述这一现象。后来的工作依赖于动物模型，证明细胞外DA在纹状体中保持在正常水平，直到损伤超过大约80%。齐格蒙德和他的同事几年来一直提出了一个令人信服的补偿假说：DA从完整区域扩散到耗竭区域，DA释放和合成的适应性增加保持了功能上的多巴胺能音调。最近的结果挑战了DA的释放、摄取和合成在该模型中所扮演的假设角色。然而，由于相互矛盾的结果还没有形成一个连贯的图景，因此很有必要确定部分去神经后纹状体中DA信号是如何保存的。该项目的总体目标是研究帕金森病临床前或无症状阶段黑质纹状体DA神经元的代偿适应。为此，将在6-羟基多巴胺损伤的大鼠中表征细胞外DA的调节，这是一种广泛使用的这种病理的动物模型。具有毫秒时间和微米空间分辨率的实时微传感器将监测由瞬时电刺激引起的细胞外DA动态。有两个具体目标。第一个目标是利用P.I.开发的新技术，在清醒的动物中评估生理频率引起的细胞外DA，以及支持这些水平的DA释放和摄取率。这些实验将扩展他之前在麻醉动物中的分析。第二个目的是确定体内DA释放和合成之间的关系。虽然DA合成的代偿性改变可能是最好的已建立的适应，但它与失神经纹状体中DA释放的关系目前仍有争议。综上所述，拟议的实验将为如何在纹状体中维持功能性多巴胺能张力提供新的见解，尽管DA神经元大量丧失。