DETERMINANTS AND CONSEQUENCES OF MDMA NEUROTOXICITY

描述（申请人摘要）：甲基苯丙胺类似物 3，4-亚甲二氧基甲基苯丙胺（MDMA）仍然是一种流行的药物， 尽管在动物和人类中有证据表明这种药物会产生长期的 对5-羟色胺（5-HT）神经元的毒性。然而，除了这一既定的 发现，MDMA产生5 HT神经毒性的机制仍然存在 未知有证据表明，MDMA通过促进氧化应激， 增加羟基自由基的形成和内源性 抗氧化剂本申请的目的是阐明本发明的实施例。 在产生羟基自由基之后或之前的过程， 是MDMA诱导的5-HT神经毒性的决定因素。此外，这是我们的 目的是将MDMA神经毒性机制与功能 脑内5-HT长期消耗的后果。总体假设 为这些研究提供基础的是，MDMA诱导的 脑5-HT由a）能量调节的破坏，B）氧化应激 促进线粒体功能障碍和细胞损伤， c）这种损伤导致5 HT受损 释放和5 HT介导的功能反应的缺陷。提供依据 支持氧化和代谢应激在MDMA诱导的5 HT中的作用 神经毒性，提出的具体目标是确定：1）MDMA 增加糖原分解和乳酸盐的形成， 线粒体酶的活性，2）MDMA的毒性是防止由 管理的能量底物和加剧线粒体 抑制剂，3）预防MDMA诱导的氧化应激（例如，羟基 自由基形成）提供对MDMA诱导的线粒体 损伤和5-HT神经毒性和4）MDMA诱导的氧化和代谢 应激导致异常的5-HT介导的功能反应，如 对药物的异常热、神经化学和行为反应 试剂或生理条件（例如，应力）。各进程之间的联系 氧化损伤和线粒体功能障碍与MDMA诱导的毒性， 5-羟色胺终末对药物诱导的神经退行性变具有重要意义 以及结果（即，风险），这可能会对滥用者的健康造成影响， 摇头丸

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.