MODEL OF PARKINSON'S DISEASE

该提案中的研究旨在确定是否轻微、 脑多巴胺能和/或症状前病变 5-羟色胺能神经元可以通过 敏感行为范式与药物的结合使用 挑战。Long-Evans大鼠将被用作实验对象，它们将 使用全身注射的神经毒素1- 甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP) 冰毒。通过改变这些毒素的剂量， 病变的大小是可以改变的。的损害程度 多巴胺能系统的范围将从0%(即对照)到 最大耗尽75%。这些多巴胺能损伤将是 伴有5-羟色胺能损害(同时由 这两种毒素)的大小从0%到大约 60%耗尽。这两种毒素都被证明是无价的 加深我们对导致经济衰退的因素的理解 中枢多巴胺能和5-羟色胺能神经元变性 因此，他们是帕金森氏症的优秀模特 疾病。然而，使用啮齿动物来探索这些模型已经 在某种程度上受到了未能证明 与毒素引起的损伤相关的行为缺陷。在……里面 然而，在这方面，PI取得了一定程度的成功 源于使用精心选择的行为范例 与药物挑战测试相结合。展示了 MPTP或甲基苯丙胺诱导的啮齿动物多巴胺能 损伤确实表现出行为缺陷，这为 验证了这些模型的有效性。

The studies in this proposal are designed to determine if slight, presymptomatic lesions of the brain dopaminergic and/or serotonergic neurons can be assessed (i.e. unmasked) through the use of sensitive behavioral paradigms combined with drug challenge. Long-Evans rats will be used as subjects and they will be treated with the systemically administered neurotoxins 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine. By varying the dose of these toxins, the magnitude of the lesion can be varied. The lesion magnitude for the dopaminergic system will range from 0% (i.e. control) to a maximum 75% depletion. These dopaminergic lesions will be accompanied by serotonergic lesions (simultaneously induced by both toxins) ranging in magnitude from 0% up to approximately 60% depletion. Both of these toxins have proven invaluable in advancing our understanding of the factors which lead to the degeneration of central dopaminergic and serotonergic neurons and, as such, have served as excellent models of Parkinson's disease. However, the use of rodents to explore these models has been somewhat restricted by the failure to demonstrate behavioral deficits associated with the toxin-induced damage. In this regard, however, the PI has obtained some degree of success stemming from use of carefully chosen behavioral paradigms used in conjunction with drug challenge tests. The demonstration that rodents with MPTP or methamphetamine-induced dopaminergic lesions do exhibit behavioral deficits has provided support for the validity of these models.