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MODEL OF PARKINSON'S DISEASE USING MPTP

使用 MPTP 建立帕金森病模型

基本信息

批准号：
3407111
负责人：
GEORGE WAGNER
金额：
$ 2.2万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-04-01 至 1988-03-31
项目状态：
已结题

项目摘要

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.

以下研究的目的是严格评估在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在许多个体中引起帕金森样症状。这观察导致了密集的努力，以开发动物模型， MPTP诱导的毒性，希望了解的病因，帕金森氏症很明显，MPTP的管理，类人灵长类动物会导致帕金森病样症状然而，最初使用大鼠和小鼠的研究得出结论，MPTP在这些物种其中一个主要问题是， MPTP后在啮齿动物中观察到的帕金森样行为症状局在这一建议中，有人认为，MPTP确实在啮齿类动物中产生明显的行为缺陷，需要行为范式来揭露这些缺陷。使用啮齿类动物而不是灵长类动物来研究MPTP诱导的毒性大大降低了费用，大量关于帕金森病啮齿动物模型的数据。例如，Carlsson关于1-多巴在逆转穿梭箱中利血平化小鼠的性能缺陷这一范例导致了1-多巴在帕金森病中的临床试验患者在初步研究中，梭箱的大量缺陷给药后，在小鼠中观察到回避反应 MPTP。 1-多巴逆转了这一缺陷。因此，第一本提案中研究的目标是复制和扩展这些初步研究结果，试图系统地评估行为 MPTP给药后的缺陷。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式这种模式提供了一个敏感的衡量罚款运动控制的主题，并作为一个很好的恭维，在梭箱中评估更多磨牙行为。因此，第二这些研究的目的是确定MPTP给药是否会引起大鼠精细运动控制的缺陷。关于帕金森氏病啮齿动物模型实用性的结论使用MPTP的疾病只能在严格和系统的评估所产生的行为缺陷，行为模式