EXCITOTOXINS AND THE NEUROTOXICITY OF AMPHETAMINES

几种苯丙胺，其中许多是流行的非法滥用药物， 对多巴胺和/或5-羟色胺能产生长期神经毒性 实验动物的神经元。有趣的是，这种类型的 单胺能神经元的损伤也依赖于两者注射的类似物 作为使用的动物的物种。目前尚不清楚为什么有些安非他明 对5-羟色胺能神经元有选择性毒性，而其他人对两者都有影响 或者仅仅是多巴胺能神经元，也不知道为什么 安非他明在小鼠和大鼠之间是不同的。此外， 这些化合物产生神经毒性的机制尚不清楚。 苯丙胺释放多巴胺(DA)和5-羟色胺(5-羟色胺)，并使其 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。另外， 甲基苯丙胺对多巴胺能神经元的损伤可以预防 通过N-甲基-D-天冬氨酸(NMDA)受体的拮抗剂， 谷氨酸受体的亚型。这些发现表明， 兴奋性毒性机制可能参与了神经毒性过程。这个 需要检验的假设是单胺类物质的促进释放 由苯丙胺导致自由基的产生和释放 兴奋性氨基酸，导致体内 多巴胺能神经末梢的氧化应激。我们的目标是 研究是为了更好地了解苯丙胺诱导的 神经病理学。拟议研究的目的是1)描述 并探讨了不同药物神经毒性差异的原因 苯丙胺对小鼠和大鼠单胺能神经元的影响 进一步评估兴奋性氨基酸和 苯丙胺对单胺能神经毒性的氧化应激 神经元和3)确定DA和5-羟色胺的释放程度 由各种苯丙胺产生，有助于多巴胺能或 5-羟色胺能毒性。这些研究将在小鼠和大鼠身上进行。 确定物种差异的特征应该有助于描绘 神经毒性的潜在机制。生化技术和 将使用药理试剂来研究 安非他明。对这一机制的理解 苯丙胺损害单胺能神经元具有重要意义 仅适用于安非他明滥用，但适用于不明原因的疾病，如 帕金森氏症、精神分裂症和抑郁症 多巴胺能和5-羟色胺能功能异常。

Several amphetamines, many of which are popular illicit drugs of abuse, produce long-term neurotoxicity to dopaminergic and/or serotonergic neurons in experimental animals. Interestingly, the type of monoaminergic neuron damaged depends on both the analog injected as well as the species of animal used. It is not known why some amphetamines are selectively toxic to serotonergic neurons whereas others affect both systems or only dopaminergic neurons nor why the neurotoxic profile for the amphetamines differs between the mouse and rat. Furthermore, the mechanisms by which these compounds produce neurotoxicity are unknown. The amphetamines 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. Additionally, methamphetamine-induced damage to dopaminergic neurons can be prevented by antagonists of the N-methyl-D-aspartate (NMDA) receptor, one of the subtypes of the glutamate receptor. These findings indicate that an excitotoxic mechanism may be involved in the neurotoxic process. The hypothesis to be tested is that the facilitated release of the monoamines by the amphetamines leads to free radical generation and a release of excitatory amino acids which results in a tremendous increase in oxidative stress in dopaminergic nerve terminals. The goal of our research is to gain a better understanding of amphetamine-induced neuropathology. The aims of the proposed studies are 1) to characterize and investigate reasons for the differential neurotoxicity of various amphetamines on monoaminergic neurons in both mice and rats, 2) to further evaluate the involvement of the excitatory amino acids and oxidative stress in amphetamines-induced toxicity to monoaminergic neurons and 3) to determine the extent to which DA and 5HT release produced by the various amphetamines contributes to dopaminergic or serotonergic toxicity.. The studies will be conducted in mice and rats. Characterizing the species differences should help to delineate the mechanisms underlying neurotoxicity. Biochemical techniques and pharmacological agents will be used to study the effects of the amphetamines. An understanding of the mechanisms by which the amphetamines 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.