EXCITOTOXINS AND THE NEUROTOXICITY OF AMPHETAMINES

几种安非他明，其中许多是普遍滥用的非法药物， 对多巴胺能和/或多巴胺能产生长期神经毒性 实验动物的神经元。 有趣的是， 单胺能神经元的损伤也依赖于注射的类似物 使用的动物种类。 目前尚不清楚为什么有些安非他明 选择性地对肾上腺素能神经元有毒，而另一些则影响两者。 系统或仅多巴胺能神经元，也没有为什么 安非他明在小鼠和大鼠之间不同。 而且 这些化合物产生神经毒性的机制尚不清楚。 安非他明释放多巴胺（DA）和5羟色胺（5 HT）， 已经假设，由氧化产生的氧衍生产物 这些单胺的氧化可能是有毒物质。 此外，本发明还 可以防止甲基苯丙胺诱导的多巴胺能神经元损伤 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂， 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神经毒性过程。 的 待检验的假设是，单胺的促进释放 导致自由基的产生和释放 兴奋性氨基酸，这导致了巨大的增加， 多巴胺能神经末梢的氧化应激。 我们的目标 研究是为了更好地了解安非他明引起的 神经病理学 拟议研究的目的是：1）表征 并研究不同的神经毒性的原因， 安非他明对小鼠和大鼠单胺能神经元的影响，2） 进一步评估兴奋性氨基酸的参与， 氧化应激在苯丙胺诱导的单胺能神经毒性中的作用 神经元和3）以确定DA和5 HT释放的程度 产生的各种安非他明有助于多巴胺能或 神经毒性。研究将在小鼠和大鼠中进行。 描述物种差异有助于描述 神经毒性的潜在机制。 生物化学技术和 药理学试剂将被用于研究的影响， 安非他明 了解这些机制， 安非他明损伤单胺能神经元具有重要意义， 仅用于安非他明滥用，但用于病因不明的疾病， 帕金森氏症，精神分裂症和抑郁症，其中有 多巴胺能和多巴胺能功能异常。

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.