LEVODOPA DYSKINESIAS: IMPACT OF DOPAMINE NEURONS

描述（由申请人提供）：最近对帕金森病（PD）的长期临床移植试验的发现表明，一部分移植受体在移植后出现加重的运动障碍。这些运动障碍是严重的，使人衰弱，并强烈表明其潜在的机制需要阐明。Freed、Fahn和同事们假设移植物介导的运动障碍是移植物过度生长造成的。然而，他们自己的PET和尸检数据，以及其他人的数据，都不支持这一观点。我们提出了另一种假设，即移植物后运动障碍的恶化是由高多巴胺能功能的局部“热点”与左旋多巴启动的大脑相互作用引起的。我们计划通过比较神经移植策略在多巴诱导的运动障碍中诱导a)广泛或b)局部高多巴胺能功能和多巴启动在帕金森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，长期服用左旋多巴的单侧多巴胺（DA）耗尽大鼠表现出与人类PD中所见的运动障碍非常相似的运动障碍特征。此外，该动物模型重要地显示了基底神经节机制，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看到的。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估，以确保这种实验性治疗既安全又有效。这种啮齿类动物模型为左旋多巴/移植物相互作用的系统评估提供了有价值的第一步。这些研究将为开展灵长类动物研究提供重要的指导方针，进一步的假设和验证可以得到检验。

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.