EXCITOTOXINS AND THE NEUROTOXICITY OF AMPHETAMINES

包括甲基苯丙胺(冰毒)在内的几种苯丙胺(AMPH)， 亚甲二氧基甲基苯丙胺(MDMA)和亚甲二氧基苯丙胺(MDA) 都是流行的滥用违禁药物。最令人担忧的是 AMPHs可能会对人类的中枢神经元造成长期损害。在……里面 实验动物的大脑，多巴胺能和/或5-羟色胺能 给予AMPHs会损害神经元。的类型 单胺能神经元的损伤既取决于注射的类似物，也取决于 所用动物的种类。目前还不清楚为什么某些类似物会产生 对5-羟色胺能神经元的优先效应或为什么有一个物种 神经细胞对AMPHs损伤敏感性的差异。 此外，这些化合物产生神经毒性的机制是 未知。AMPH释放多巴胺(DA)和5-羟色胺(5-羟色胺)，并 已经假设氧气衍生产品是由 这些单胺的氧化可能是有毒物种。我们最近发现 冰毒对多巴胺能神经元的损伤可以通过 N-甲基-D-天冬氨酸拮抗剂对小鼠的保护作用 受体，谷氨酸受体的一个亚型。这些发现 提示兴奋性氨基酸(EaAs)可能参与冰毒诱导 多巴胺能毒性。我们的工作假设是，由 冰毒会导致自由基的产生和EaS的大量释放 导致多巴胺能神经氧化应激显著增加 终点站。这项研究的目的是为了更好地了解 AMPHs如何产生毒性，研究EaaS和EaAs的参与 氧化应激在它们的毒性中，来研究为什么有一个 不同类似物对多巴胺能和5-羟色胺能的不同作用 神经元，并研究为什么大鼠的5-羟色胺能神经元 对苯丙胺引起的损伤比小鼠更敏感。 将使用生化技术和药理试剂来研究 AMPHS的行动。对AMPH的作用机制的理解 损伤单胺能神经元不仅对 滥用安非他明，但用于原因不明的疾病，如帕金森氏症 疾病、精神分裂症和抑郁症，其中有异常的 多巴胺和5-羟色胺能功能。

Several amphetamines (AMPHs) including methamphetamine (METH), methylenedioxymethamphetamine (MDMA) and methylenedioxyamphetamine (MDA) are popular illicit drugs of abuse. Of great concern is the possibility that the AMPHs may cause long-term damage to central neurons in humans. In the brains of experimental animals, dopaminergic and/or serotonergic neurons are damaged by administration of the AMPHs. The type of monoaminergic neuron damaged depends on both the analog injected as well as the species of animal used. It is not clear why certain analogs exert preferential effects on serotonergic neurons or why there is a species difference in the susceptibility of neurons to damage by the AMPHs. Moreover, the mechanisms by which these compounds produce neurotoxicity are unknown. The AMPHs release both dopamine (DA) and serotonin (5HT) and it has been hypothesized that oxygen-derived products resulting from the oxidation of these monoamines may be the toxic species. We recently found that METH-induced damage to dopaminergic neurons can be prevented by pretreatment of mice with antagonists of the N-methyl-D-aspartate (NMDA) receptor, one of the subtypes of the glutamate receptor. These findings indicate that excitatory amino acids (EAAs) may be involved in METH-induced dopaminergic toxicity. Our working hypothesis is that the DA released by METH leads to free radical generation and a large release of EAAs which results in a tremendous increase in oxidative stress in dopaminergic nerve terminals. The aims of this research are to gain a greater understanding of how the AMPHs produce toxicity, to study the involvement of EAAs and oxidative stress in their toxicities, to investigate why there is a differential effect of the various analogs on dopaminergic and serotonergic neurons, and to examine why the serotonergic neurons in the rat are so much more susceptible to amphetamine-induced damage than those in the mouse. Biochemical techniques and pharmacological agents will be used to study the actions of the AMPHS. An understanding of the mechanisms by which the AMPHs damage monoaminergic neurons has important implications not only for amphetamine abuse but for disorders of unknown etiology such as Parkinson's Disease, schizophrenia and depression in which there are abnormalities in dopaminergic and serotonergic function.