MDMA NEUROTOXICITY IN HUMANS-- OCCURENCE & CONSEQUENCE

MDMA 对人类的神经毒性——发生情况

• 批准号: 6121402
• 负责人: GEORGE A RICAURTE
• 金额: $ 6.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6121402
• 关键词: 3,4 methylenedioxymethamphetamine; cellular pathology; clinical research; drug abuse; epidemiology; human subject; neurons; neurotoxicology; serotonin

3,4-methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative used recreationally by humans. Despite its illicit status and knowledge that MDMA is highly neurotoxic to brain serotonin systems in animals, reports of human MDMA have increased. The purpose of this project is twofold: 1) to confirm and extend data suggesting that recreational MDMA users incur damage to central serotonin neurons; and 2) to further probe for functional consequences of MDMA GRexposure. In particular, biochemical and fucntional studies will be performed in a controlled inpatient setting to address the following specific questions: 1) Biochemical Studies: a) using CSF measurements of monoamine metabolites, can it be determined: (i) whether MDMA neurotoxicity is dose (exposure) related; (ii) whether there are sex differences in the response to MDMA neurotoxicity; and (iii) whether CSF HVA is also reduced in MDMA users with greatest exposure. b) Using neuroendocrine challenge with m-CPP, can MDMA-induced alterations in brain serotonin innervation be detected (i.e., are prolactin and/or cortisol responses altered?). 2) Functional Studies: a) Do MDMA users have altered mood, anxiety, temperature, or cognitive responses to pharmacological (m-CPP) challenge? b) Can alterations in mood, anxiety, and cognition (behavioral domains that putatively involve serotonin) be detected in MDMA users in response to physicochemical challenge (tryptophan depletion)? c) Are the previously noted alterations of sleep architecture in MDMA users exacerbated following tryptophan depletion, and does m-CPP differentially affect sleep in MDMA users and controls? d) Do MDMA users have an altered response to ischemic or thermal pain, and is their analgesic response to morphine altered? e) Can differences in impulsivity and hostility that were previously observed in MDMA users be confirmed and extended using other research instruments? By addressing these questions, this research will test the hypothesis that MDMA neurotoxicity generalizes to humans, and that toxicity has functional consequences. The long-term goals of this project are to better delineate the public health resks of recreational MDMA use, and to utilize this unique population of individuals to further elucidate the role of brain serotonin in health and disease.

3，4-亚甲二氧基甲基苯丙胺（MDMA）是一种合成苯丙胺衍生物，用于人类娱乐。尽管二亚甲基双氧安非他明处于非法地位，而且人们也知道二亚甲基双氧安非他明对动物大脑5-羟色胺系统具有高度神经毒性，但关于人用二亚甲基双氧安非他明的报告仍有所增加。该项目的目的有两个：1）确认和扩展表明娱乐性MDMA使用者对中枢5-羟色胺神经元造成损害的数据; 2）进一步探索MDMA GR暴露的功能后果。特别是，将在对照住院患者中进行生化和功能研究，以解决以下具体问题：1）生化研究：a）使用单胺代谢物的CSF测量值，能否确定：（i）MDMA神经毒性是否与剂量（暴露）相关;（ii） 是否有性别差异的反应MDMA神经毒性;（iii）是否CSF HVA也减少MDMA用户与最大的曝光。B） 使用m-CPP的神经内分泌激发，是否可以检测到MDMA诱导的脑5-羟色胺神经支配的改变（即，催乳素和/或皮质醇反应是否改变？）。2)功能研究：a）MDMA使用者是否对药理学（m-CPP）挑战改变了情绪、焦虑、体温或认知反应？B）MDMA使用者在接受理化激发（色氨酸耗竭）后，是否可以检测到情绪、焦虑和认知（与血清素有关的行为领域）的改变？c）MDMA使用者睡眠结构的改变是否在色氨酸耗尽后加剧，m-CPP是否对MDMA使用者和对照者的睡眠有不同的影响？（d）摇头丸使用者 对缺血性疼痛或热痛的反应改变，他们对吗啡的镇痛反应是否改变？e）以前在MDMA使用者中观察到的冲动和敌意的差异是否可以使用其他研究工具来证实和扩展？通过解决这些问题，这项研究将测试的假设，MDMA神经毒性普遍适用于人类，毒性有功能的后果。该项目的长期目标是更好地描述娱乐性MDMA使用的公共卫生风险，并利用这一独特的人群进一步阐明大脑5-羟色胺在健康和疾病中的作用。