Dopamine Neurotransmission in Experimental Parkinsonism

描述(申请人提供)：帕金森病是一种衰弱的神经病理，与黑质纹状体多巴胺能神经元的丧失有关。有趣的是，静止性震颤、僵硬和动作迟缓的主要症状直到广泛失神经才会出现。动物研究表明，运动功能是通过维持多巴胺能张力来正常化的，多巴胺能张力是脑细胞外液中多巴胺的环境浓度。在多巴胺能神经元几乎完全丧失的情况下，如何保持多巴胺能张力一直是Pi Garris以前工作的重点。在这个项目中，人们将致力于研究在多巴胺严重耗竭的纹状体中，为什么多巴胺能信号失灵以及L-多巴是如何发挥作用的。L-多巴是目前治疗帕金森氏症的主要药物。伏安法微型传感器实验将在动物模型6-羟基多巴胺损伤的大鼠中进行。这些探针以毫秒的时间和微米的空间分辨率监测多巴胺，允许直接评估细胞外多巴胺能神经传递、释放、摄取和扩散的中枢机制。特异性目标1表征DA释放和摄取的代偿适应，以及DA扩散、合成和代谢之间的关系。我们的目标是更全面地了解多巴胺能信号。特异性目标2表征L多巴对DA的释放、摄取和扩散的影响，以及对紧张性和相性多巴胺能信号的影响。强直信号会产生多巴胺能音，而时相信号会在周围的多巴胺水平上产生短暂的浓度峰值。相位信号被显著的刺激激活，被认为对联想学习很重要。这项拟议的研究意义重大，因为人们对严重受损的纹状体中多巴胺能信号如何失败以及为什么失败知之甚少。此外，L多巴在长期使用后会出现不良反应，显然是由于非生理性的多巴胺替代所致。然而，L-多巴是如何作用于多巴胺能信号的还没有完全确定。

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.