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Dopamine Neurotransmission in Experimental Parkinsonism

实验性帕金森症中的多巴胺神经传递

基本信息

批准号：
6954466
负责人：
PAUL A GARRIS
金额：
$ 21万
依托单位：
ILLINOIS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-05-15 至 2009-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease is a debilitating neuropathology associated with the loss of nigrostriatal dopaminergic neurons. Interestingly, cardinal symptoms of resting tremor, rigidity and akinesia do not occur until denervation is extensive. Animal studies indicate that motor function is normalized by the maintenance of dopaminergic tone, the ambient concentration of dopamine in brain extracellular fluid. How dopaminergic tone is maintained despite the near complete loss of dopaminergic neurons has been the focus of previous work by PI Garris. In this project, efforts will be directed at examining, in the severely dopamine-depleted striatum, why dopaminergic signaling fails and how L-DOPA acts. L-DOPA is the primary medication used to treat Parkinson's disease today. Voltammetric microsensor experiments will be performed in an animal model, the 6-hydroxydopamine-lesioned rat. These probes, monitoring dopamine with millisecond temporal and micron spatial resolution, permit direct assessment of the central mechanisms of extracellular dopaminergic neurotransmission, release, uptake and diffusion. Specific Aim 1 characterizes compensatory adaptation of DA release and uptake, and the relationship between DA diffusion, synthesis and metabolism. The goal is a more comprehensive view of dopaminergic signaling. Specific Aim 2 characterizes the effects of L-DOPA on DA release, uptake and diffusion, and on tonic and phasic dopaminergic signaling. Whereas tonic signaling generates dopaminergic tone, phasic signaling produces a transient concentration spike on top of ambient dopamine levels. Phasic signaling is activated by salient stimuli and thought to be important for associative learning. The proposed research is significant, because how and why dopaminergic signaling fails in the severely lesioned striatum is poorly understood. Moreover, L-DOPA is associated with adverse side effects after extended use, apparently due to non-physiological dopamine replacement. However, how L-DOPA acts on dopaminergic signaling is not completely established.

描述（由申请人提供）：帕金森病是一种衰弱的神经病理学，与黑质纹状体多巴胺能神经元的丧失有关。有趣的是，静息性震颤、强直和运动障碍等主要症状直到神经支配广泛失支配时才会出现。动物研究表明，通过维持多巴胺能张力，即脑细胞外液中多巴胺的环境浓度，运动功能得以正常化。尽管多巴胺能神经元几乎完全丧失，但多巴胺能张力如何维持一直是PI Garris先前工作的重点。在这个项目中，将致力于在多巴胺严重缺乏的纹状体中检查多巴胺能信号传导失败的原因以及左旋多巴如何起作用。左旋多巴是目前治疗帕金森病的主要药物。伏安微传感器实验将在6-羟多巴胺损伤大鼠动物模型上进行。这些探针以毫秒时间和微米空间分辨率监测多巴胺，可以直接评估细胞外多巴胺能神经传递、释放、摄取和扩散的中心机制。Specific Aim 1描述了DA释放和摄取的代偿性适应，以及DA扩散、合成和代谢之间的关系。目标是对多巴胺能信号传导有一个更全面的认识。特异性目标2描述了左旋多巴对DA释放、摄取和扩散的影响，以及对强直和相位多巴胺能信号传导的影响。强直信号产生多巴胺能张力，而相位信号产生瞬时的多巴胺浓度峰值。相位信号被显著刺激激活，被认为对联想学习很重要。提出的研究是重要的，因为如何和为什么多巴胺能信号在严重受损纹状体失败尚不清楚。此外，长期使用左旋多巴与不良副作用相关，显然是由于非生理性多巴胺替代。然而，左旋多巴是如何作用于多巴胺能信号的尚未完全确定。