MODEL OF PARKINSON'S DISEASE

本提案中的研究旨在确定是否轻微， 脑多巴胺能的症状前病变和/或 可以通过免疫组织化学方法评估（即，未掩蔽）多巴胺能神经元。 使用敏感的行为模式结合药物 挑战. Long-Evans大鼠将被用作受试者， 用全身施用的神经毒素1- 甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）或 冰毒 通过改变这些毒素的剂量， 损伤的大小可以变化。 损伤程度 多巴胺能系统将在0%（即对照）至 最多消耗75% 这些多巴胺能损伤 伴随着肾上腺素能病变（同时诱导 这两种毒素）的数量级从0%到大约 消耗了60%。 这两种毒素都被证明是无价的， 提高我们对导致 中枢多巴胺能和多巴胺能神经元变性 因此，它们是帕金森病的优秀模型， 疾病 然而，使用啮齿动物来探索这些模型， 由于未能证明 与毒素引起的损伤有关的行为缺陷。 在 然而，在这方面，PI已经取得了一定程度的成功 源于使用精心选择的行为范式 与药物激发试验相结合。 的示威 具有MPTP或甲基苯丙胺诱导的多巴胺能 病变确实表现出行为缺陷，这为 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.