DETERMINANTS AND CONSEQUENCES OF MDMA NEUROTOXICITY

说明(申请人摘要)：甲基苯丙胺类似物 3，4-亚甲基二氧基甲基苯丙胺(MDMA)继续是一种受欢迎的药物 虐待，尽管在动物和人类中有证据表明这种制剂会产生长期的 对5-羟色胺(5-HT)神经元的毒性。然而，除了这一久负盛名的 研究发现，MDMA产生5-羟色胺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 ··· 抗氧化剂。本申请的目的是阐明 羟基自由基产生之前或之后的过程 是MDMA诱导的5-羟色胺神经毒性的决定因素。而且，它是我们的 目的将MDMA的神经毒性机制与功能性 脑内5-羟色胺长期耗竭的后果。总体假设 这为这些研究提供了基础，那就是MDMA诱导的 大脑5-羟色胺的结果是a)能量调节中断，b)氧化应激 这会促进线粒体功能障碍和细胞损伤 伴随这些过程，以及c)这种损伤会导致5羟色胺受损 5-羟色胺介导的功能反应的释放和缺失。提供证据 氧化和代谢应激在MDMA诱导的5-羟色胺中的作用 神经毒性提出了具体目标，以确定1)MDMA 增加糖原分解和乳酸的形成，并降低 线粒体酶活性，2)MDMA毒性可通过 能量底物的给药和线粒体的加重 抑制剂，3)防止MDMA诱导的氧化应激(例如，羟基 自由基形成)提供对MDMA诱导的线粒体的保护 损伤和5-羟色胺的神经毒性以及4)MDMA诱导的氧化和代谢 应激导致异常的5-羟色胺介导的功能反应，表现为 对药物的异常体温、神经化学和行为反应 诱因或生理条件(例如，压力)。流程的联动 氧化损伤和线粒体功能障碍与MDMA诱导的毒性 5-羟色胺终末在药物诱导的神经退行性变中有重要意义 以及这可能对滥用药物者的健康造成的后果(即风险) 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.