DETERMINANTS AND CONSEQUENCES OF MDMA NEUROTOXICITY

MDMA 神经毒性的决定因素和后果

• 批准号: 6706925
• 负责人: GARY GUDELSKY
• 金额: $ 24.62万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-15 至 2006-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6706925
• 关键词: 3,4 methylenedioxymethamphetamine; cytotoxicity; free radicals; glycogenolysis; high performance liquid chromatography; laboratory rat; microdialysis; mitochondria; neuropharmacologic agent; neurotoxicology; neurotransmitter metabolism; oxidative stress; pharmacokinetics; serotonin

DESCRIPTION (applicant's abstract): The methamphetamine analog 3,4-methylenedioxymethamphetamine (MDMA) continues to be a popular drug of abuse despite evidence in animals and humans that this agent produces long-term toxicity to serotonin (5HT) neurons. However, beyond this well-established finding, the mechanisms through which MDMA produces 5HT neurotoxicity remains unknown. There is evidence that MDMA promotes oxidative stress through the increased formation of hydroxyl radicals and depletion of endogenous antioxidants. The intent of the present application is to elucidate the processes, subsequent to or preceding the generation of hydroxyl radicals, that are the determinants of MDMA-induced 5HT neurotoxicity. Moreover, it is our intent to relate the mechanisms of MDMA neurotoxicity to the functional consequences of the long-term depletion of brain 5HT. The overall hypothesis that provides the basis for these studies is that the MDMA-induced depletion of brain 5HT results from a) disruption of energy regulation, b) oxidative stress that promotes mitochondrial dysfunction and the cellular damage that accompanies these processes and c) that such damage results in impaired 5HT release and deficits in 5HT-mediated functional responses. To provide evidence in support of the roles of oxidative and metabolic stress in MDMA-induced 5HT neurotoxicity the specific aims are proposed to establish that 1) MDMA increases glycogenolysis and the formation of lactate and decreases the activity of mitochondrial enzymes, 2) MDMA toxicity is prevented by the administration of energy substrates and exacerbated by mitochondrial inhibitors, 3) prevention of MDMA-induced oxidative stress (e.g., hydroxyl radical formation ) offers protection against MDMA-induced mitochondrial impairment and 5HT neurotoxicity and 4) MDMA-induced oxidative and metabolic stress results in abnormal 5HT mediated functional responses, as manifested by abnormal thermal, neurochemical and behavioral responses to pharmacological agents or physiological conditions (e.g., stress). The linkage of the processes of oxidative damage and mitochondrial dysfunction with MDMA-induced toxicity to 5HT terminals has significant implications for drug-induced neurodegeneration and the consequences (i.e., risk) this may impose on the health of abusers of MDMA.

描述（申请人的摘要）：甲基苯丙胺类似物 3,4-甲基二甲基甲基苯丙胺（MDMA）仍然是一种流行的药物 尽管动物和人类有证据表明该代理人长期产生虐待 对5-羟色胺（5HT）神经元的毒性。但是，除了这个良好的 发现MDMA产生5HT神经毒性的机制仍然存在 未知。有证据表明MDMA通过 羟基自由基的形成增加和内源性的耗竭 抗氧化剂。本应用的目的是阐明 在羟基自由基产生之前或之前的过程， 是MDMA诱导的5HT神经毒性的决定因素。而且，这是我们的 意图将MDMA神经毒性的机制与功能 大脑5HT长期耗竭的后果。总体假设 为这些研究提供了基础，是MDMA诱导的耗竭 大脑5HT是由A）氧化应激的破坏而导致的。 促进线粒体功能障碍和细胞损伤 伴随这些过程，c）这种损害导致5HT受损 5HT介导的功能响应中的释放和缺陷。提供证据 支持氧化和代谢应激在MDMA诱导的5HT中的作用 神经毒性提出了具体目的以确定1）MDMA 增加糖原分解和乳酸的形成，并减少 线粒体酶的活性，2）MDMA毒性由 能量底物给药并通过线粒体加剧 抑制剂3）预防MDMA诱导的氧化应激（例如羟基 激进的形成）提供了防止MDMA诱导的线粒体的保护 损伤和5HT神经毒性以及4）MDMA诱导的氧化和代谢 压力导致异常5HT介导的功能反应，这表明 对药理的异常热，神经化学和行为反应 药物或生理条件（例如，压力）。过程的联系 氧化损伤和线粒体功能障碍，具有MDMA诱导的毒性 5HT末端对药物诱导的神经退行性有重要影响 以及后果（即风险），这可能对 MDMA。