MODEL OF PARKINSON'S DISEASE USING MPTP

以下研究的目标是严格评估 帕金森病啮齿动物模型中观察到的行为缺陷 使用1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)。暴露于 MPTP在一些人中引起了帕金森样症状。这 观察导致了一项密集的努力，以发展动物模型 MPTP诱导的毒性，希望了解其病因 帕金森氏症。显然，MPTP的管理是为了 非人灵长类动物会导致类似帕金森症的症状。但是，首字母 使用大鼠和小鼠的研究得出结论，MPTP在这些疾病中没有作用 物种。其中一个主要问题是，没有公开的 MPTP后观察到的啮齿动物帕金森样行为症状 行政管理。在这项提案中，有人认为MPTP确实 在啮齿动物中产生明显的行为缺陷，但更敏感 要揭露这些缺陷，就需要行为范式。 使用啮齿动物而不是非人灵长类动物来 研究MPTP引起的毒性大大减少了费用， 关于帕金森氏症啮齿动物模型的大量数据已经可用。 例如，Carlsson关于1-多巴在体内的作用的经典工作 在穿梭箱中逆转利血平注射小鼠的性能缺陷 帕金森氏病1-多巴的临床试验 病人。在初步研究中，穿梭旅行箱的巨大赤字 在给药后的小鼠中观察到回避反应 MPTP。这一缺陷被1-多巴逆转。因此，第一个 这项建议中研究的目标是复制和推广这些 试图系统地评估行为的初步发现 给大鼠注射MPTP后出现的缺陷。 第二种行为范式，已被用于分析 与大脑多巴胺耗竭相关的行为缺陷是 杠杆范例。这一范例提供了一种对罚款的敏感衡量 对受试者的运动控制，这是对 在穿梭箱中评估更多的摩尔行为。因此，第二个 这些研究的目的是确定MPTP管理是否会导致 大鼠在精细运动控制方面的缺陷。 关于帕金森病啮齿动物模型实用性的结论 疾病使用MPTP后才能做出严谨和系统的 对由此产生的行为缺陷的评估，以敏感度衡量 行为范式。

The objective of the following studies is to rigorously evaluate the behavioral deficits observed in the rodent model of Parkinson's Disease using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Exposure to MPTP caused parkinsonian-like symptoms in a number of individuals. This observation has led to an intensive effort to develop animal models of MPTP-induced toxicity in the hope of gaining insight into the etiology of Parkinson's Disease. It is clear that the administration of MPTP to subhuman primates causes the parkinsonian-like symptoms. However, initial studies using rats and mice concluded that MPTP was without effect in these species. One of the major issues was that there were no overt parkinsonian-like behavioral symptoms observed in rodents following MPTP administration. In this proposal, it is argued that MPTP does indeed produce marked behavioral deficits in rodents but, more sensitive behavioral paradigms are required to unmask these deficits. Among the advantages of using rodents rather than subhuman primates to study MPTP-induced toxicity are substantially reduced expenses and the wealth of data already available on rodent models of Parkinson's Disease. For example, the classic work of Carlsson on the effects of 1-dopa in reversing performance deficits of reserpinized mice in the shuttle box paradigm led to the clinical trials of 1-dopa in Parkinson's Disease patients. In preliminary studies, a substantial deficit in shuttle box avoidance responding was observed in mice following the administration of MPTP. The deficit was reversed by 1-dopa. Accordingly, the first objective of the studies in this proposal is to replicate and extend these initial findings in an attempt to systematically evaluate the behavioral deficits following MPTP administration to rats. A second behavioral paradigm which has been employed for the analysis of behavioral deficits associated with brain dopamine depletions is the force lever paradigm. This paradigm provides a sensitive measure of the fine motor control of the subject and serves as an excellent compliment to the more molar behaviors assessed in the shuttle box. Accordingly, the second objective of these studies is to determine if MPTP administration causes a deficit in fine motor control of the rat. Conclusions concerning the utility of the rodent model of Parkinson's Disease using MPTP can be made only after a rigorous and systematic evaluation of the resulting behavioral deficits as measured in sensitive behavioral paradigms.