Dopamine Neurotransmission in Experimental Parkinsonism

描述（由申请人提供）：帕金森病（PD）是一种毁灭性的神经病理学，沿着美国近100万人以及全世界数百万人受到折磨。典型的三重症状，静止性震颤，僵硬和运动不能，通常发生在生命的第五和第六个十年。有趣的是，尽管PD与大脑中黑质纹状体多巴胺（DA）神经元的变性明显相关，但直到纹状体DA几乎完全丧失（> 80%）时才出现症状。事实上，在症状变得明显之前，需要超过90%的病变。尽管广泛的神经退行性变，但正常运动功能的维持表明存在有效的代偿机制。在PD研究的早期，Hornykiewicz和同事创造了“适应能力”来描述这种现象。后来的工作，依赖于动物模型，证明细胞外DA在纹状体中维持在正常水平，直到病变超过约80%。Zigmond和同事们已经开发了几年来似乎令人信服的补偿假说：DA从完整区域扩散到耗尽区域，DA释放和合成的适应性增加保留了功能性多巴胺能张力。最近的研究结果挑战了DA释放，摄取和合成在这个模型中所扮演的假设角色。由于一个连贯的画面还没有出现从矛盾的结果，然而，有一个很大的需要，以建立如何DA信号是保存在纹状体后，部分去神经。该项目的总体目标是研究PD临床前或无症状阶段黑质纹状体DA神经元的代偿性适应。为此，将在6-羟基多巴胺损伤大鼠中表征细胞外DA的调节，6-羟基多巴胺损伤大鼠是这种病理学的广泛使用的动物模型。具有毫秒级时间和微米级空间分辨率的实时微传感器将监测瞬时电刺激引起的细胞外DA动态。有两个具体目标。第一个目的是使用P.I.开发的新技术在清醒动物中评估由生理频率诱发的细胞外DA，以及支持这些水平的DA释放和摄取速率。这些实验将扩展他以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合成的代偿性变化可能是最好的适应，但其与去神经纹状体DA释放的关系目前仍有争议。两者合计，拟议的实验将产生新的见解如何维持功能性多巴胺能神经元的广泛损失，尽管在纹状体。

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.