LEVODOPA DYSKINESIAS: IMPACT OF DOPAMINE NEURONS

描述（由申请人提供）：帕金森病（PD）长期临床移植试验的最新发现表明，部分移植受体发生了移植后运动障碍加重。这些运动障碍是严重的，使人衰弱的，强烈表明需要阐明它们的潜在机制。Freed、Fahn及其同事假设移植物过度生长导致移植物介导的运动障碍。然而，他们自己的PET和尸检数据，以及其他人的数据，并不支持这一观点。我们提出了一个替代假设，移植后运动障碍的恶化是由于局部多巴胺能功能亢进与左旋多巴引发的大脑相互作用的“热点”。我们计划通过比较在多巴胺诱导的运动障碍后诱导a）广泛或B）局部高多巴胺能功能的神经移植策略以及多巴胺引发在帕金森病大鼠模型中的作用来验证这一假设。我们和其他人已经证明，单方面多巴胺（DA）耗尽的大鼠长期治疗左旋多巴表现出运动障碍的特点非常相似，在人类PD中看到的运动障碍。此外，该动物模型重要地显示了基底神经节机制，其允许DA移植物加重（Steece-Collier等人，提交）或改善这些运动障碍指数，类似于在人类移植物受体中所见。在继续临床使用之前，需要对神经移植与左旋多巴运动障碍的相互作用进行系统评价，以确保这种实验性治疗安全有效。这种啮齿动物模型提供了一个有价值的第一步，左旋多巴/移植物相互作用的系统评价。这些研究将提供重要的指导方针，在发展灵长类动物的研究，进一步的假设和验证可以测试。

DESCRIPTION (provided by applicant): Recent findings from long-term clinical grafting trials for Parkinson's disease (PD) show that a portion of graft recipients develop aggravated post-graft dyskinesias. These dyskinesias are severe, debilitating and strongly indicate that mechanisms underlying them need to be elucidated. Freed, Fahn and coworkers have hypothesized that grafted-mediated dyskinesias result from graft overgrowth. However, their own PET and post-mortem data, as well as the data from others, do not support this view. We propose an alternative hypothesis that post-graft worsening of dyskinesias result from local "hot spots" of hyperdopaminergic function interacting with the levodopa primed brain. We plan to test this hypothesis by comparing neural grafting strategies that induce either a) widespread or b) local hyperdopaminergic function upon dopa-induced dyskinesias AND the role of dopa priming in a rat model of parkinsonism. We, and others have demonstrated that unilaterally dopamine (DA) depleted rats chronically treated with levodopa exhibit dyskinesias with characteristics remarkably similar to the dyskinesias seen in human PD. Further, this animal model importantly displays basal ganglia mechanisms that allow for DA grafts to either accentuate (Steece-Collier et al, submitted) or ameliorate these dyskinesia indices, similar to that seen in human graft recipients. Prior to continued clinical use, a systematic evaluation of the interaction of neural grafting with levodopa dyskinesias is needed to ensure that this experimental therapy is both safe and effective. This rodent model provides a valuable first step in such a systematic evaluation of levodopa/graft interactions. These studies will provide important guidelines useful in developing primates studies where further hypotheses and verification can be tested.