MDMA NEUROTOXICITY IN HUMANS-- OCCURENCE & CONSEQUENCE

3,4-亚甲基二氧甲基苯丙胺（MDMA）是一种合成的安非他明衍生物，被人类用于娱乐。尽管MDMA的非法地位和已知MDMA对动物脑血清素系统具有高度神经毒性，但关于人类MDMA的报道有所增加。该项目的目的有两个：1)证实和扩展娱乐性MDMA使用者对中枢血清素神经元造成损害的数据；2)进一步探讨MDMA暴露对功能的影响。特别是，生化和功能研究将在受控的住院病人环境中进行，以解决以下具体问题：1)生化研究：a)使用单胺代谢物的脑脊液测量，可以确定：(i) MDMA神经毒性是否与剂量（暴露）相关；（ii）对MDMA神经毒性的反应是否有性别差异；（iii）最大暴露量的MDMA使用者CSF HVA是否也降低。b)使用m-CPP的神经内分泌挑战，mdma诱导的脑5 -羟色胺神经支配的改变是否可以被检测到（即，催乳素和/或皮质醇反应是否改变？）2)功能研究：a) MDMA使用者对药理学（m-CPP）挑战是否会改变情绪、焦虑、体温或认知反应？b) MDMA使用者对理化挑战（色氨酸耗竭）的反应能否检测到情绪、焦虑和认知（假定涉及血清素的行为领域）的改变？c) MDMA使用者先前注意到的睡眠结构改变是否在色氨酸耗尽后加剧，m-CPP对MDMA使用者和对照组的睡眠影响是否存在差异？d) MDMA使用者对缺血性或热痛的反应是否有改变，他们对吗啡的镇痛反应是否有改变？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用其他研究工具证实和扩展？通过解决这些问题，本研究将验证MDMA神经毒性对人类的普遍性，以及毒性具有功能后果的假设。该项目的长期目标是更好地描述娱乐性使用MDMA的公共健康风险，并利用这一独特的个体群体进一步阐明脑血清素在健康和疾病中的作用。

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.