MDMA NEUROTOXICITY IN HUMANS-- OCCURENCE & CONSEQUENCE

3，4-亚甲基二氧基甲基苯丙胺(MDMA)是一种人工合成的苯丙胺衍生物，供人类娱乐使用。尽管MDMA处于非法状态，而且知道MDMA对动物的大脑5-羟色胺系统具有高度神经毒性，但有关人类MDMA的报告有所增加。该项目的目的有两个：1)证实和扩展娱乐MDMA使用者造成中枢5-羟色胺神经元损伤的数据；2)进一步探讨MDMA GR暴露的功能后果。特别是，生化和功能研究将在受控住院患者环境中进行，以解决以下具体问题：1)生化研究：a)使用脑脊液对单胺代谢物的测量，能否确定：(I)MDMA神经毒性是否与剂量(暴露)有关；(Ii)对MDMA神经毒性的反应是否存在性别差异；以及(Iii)在MDMA使用者中，接触最多的人的脑脊液HVA是否也减少。B)使用m-CPP进行神经内分泌激发，能否检测到MDMA引起的脑内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使用者对药物(m-CPP)的挑战是否改变了情绪、焦虑、体温或认知反应？B)MDMA使用者的情绪、焦虑和认知(可能涉及5-羟色胺的行为领域)是否可以检测到对物理化学挑战(色氨酸耗竭)的反应？C)之前提到的MDMA使用者的睡眠结构改变是否在色氨酸耗竭后加剧，以及m-CPP是否对MDMA使用者和对照组的睡眠有不同的影响？D)MDMA使用者对缺血或热痛的反应是否改变，他们对吗啡的止痛反应是否改变？E)以前在摇头丸使用者身上观察到的冲动和敌意方面的差异是否可以用其他研究工具来证实和推广？通过解决这些问题，这项研究将检验MDMA神经毒性普遍适用于人类以及毒性具有功能性后果的假设。该项目的长期目标是更好地描述娱乐性MDMA使用对公共健康的影响，并利用这一独特的个体群体进一步阐明大脑5-羟色胺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.