Dopamine Neurotransmission in Experimental Parkinsonism

点击翻译按钮获取中文摘要

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.