EXCITOTOXINS AND THE NEUROTOXICITY OF AMPHETAMINES

兴奋毒素和安非他明的神经毒性

• 批准号: 3212835
• 负责人: Patricia K Sonsalla
• 金额: $ 15.48万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3212835
• 关键词: 3,4 methylenedioxymethamphetamine; NMDA receptors; amphetamines; central nervous system stimulants; dopamine; dopamine receptor; drug abuse; free radical oxygen; glutamates; inhibitor /antagonist; laboratory mouse; laboratory rat; methamphetamine; neural degeneration; neurotoxins; neurotransmitter metabolism; oxidation reduction reaction; oxidative stress; serotonin; serotonin receptor

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.

几种包括甲基苯丙胺（甲基苯丙胺）的苯丙胺（AMPH）， 甲基二甲基甲基苯丙胺（MDMA）和甲基二乙酰苯丙胺（MDA） 是流行的非法虐待药物。非常关心的是可能性 AMPHS可能会对人类中央神经元造成长期损害。在 实验动物，多巴胺能和/或血清素能的大脑 神经元被AMPHS的给药损坏。类型 单胺能神经元受损的神经元均取决于注射的类似物以及 动物的种类。目前尚不清楚为什么某些类似物会施加 对血清素能神经元的优先影响，或者为什么有一个物种 神经元对AMPH损伤的敏感性差异。 此外，这些化合物产生神经毒性的机制是 未知。 AMPHS释放多巴胺（DA）和5-羟色胺（5HT），并且 已经假设 这些单胺的氧化可能是有毒物种。我们最近发现 甲基甲基对多巴胺能神经元的损害可以通过 用N-甲基-D-天冬氨酸（NMDA）的拮抗剂对小鼠预处理 受体，谷氨酸受体的亚型之一。这些发现 表明兴奋性氨基酸（EAA）可能参与了甲基氨基酸 多巴胺能毒性。我们的工作假设是发行的DA 冰毒导致自由基一代和大量的EAA释放 导致多巴胺能神经的氧化应激大大增加 终端。这项研究的目的是对 AMPHS如何产生毒性，研究EAA和 其毒性中的氧化应激，以研究为什么有 各种类似物对多巴胺能和血清素能的差异效应 神经元，并检查为什么大鼠中的血清素能神经元如此之多 比小鼠中的苯丙胺诱导的损伤更容易受到损害。 生化技术和药理学剂将用于研究 AMPHS的动作。对AMPHS的机制的理解 损害单胺能神经元不仅对 苯丙胺滥用，但由于帕金森氏病等未知病因的疾病 疾病，精神分裂症和抑郁症中存在异常 多巴胺能和血清素能功能。