MDMA NEUROTOXICITY IN HUMANS: OCCURRENCE AND CONSEQUENCES

MDMA 对人类的神经毒性：发生情况和后果

• 批准号: 7375788
• 负责人: GEORGE A RICAURTE
• 金额: $ 19.64万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7375788
• 关键词: MDMA; NEUROTOXICITY; HUMANS; OCCURRENCE; CONSEQUENCES

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 exposure. 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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。 3,4-亚甲基二氧基甲基苯丙胺 (MDMA) 是一种供人类娱乐使用的合成苯丙胺衍生物。尽管 MDMA 属于非法状态，并且人们知道 MDMA 对动物大脑血清素系统具有高度神经毒性，但人类 MDMA 的报道有所增加。该项目的目的有两个：1）确认和扩展表明娱乐性 MDMA 使用者对中枢血清素神经元造成损害的数据； 2) 进一步探讨 MDMA 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) 使用单胺代谢物的 CSF 测量，是否可以确定： (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存在性别差异； (iii) 接触 MDMA 最多的使用者中，CSF HVA 是否也会减少。 b) 使用 m-CPP 进行神经内分泌激发，可以检测 MDMA 诱导的大脑血清素神经支配的改变（即催乳素和/或皮质醇反应是否改变？）。 2) 功能研究： a) MDMA 使用者对药理学 (m-CPP) 挑战的情绪、焦虑、体温或认知反应是否发生改变？ b) 能否在 MDMA 使用者中检测到因理化挑战（色氨酸消耗）而导致的情绪、焦虑和认知（推测涉及血清素的行为领域）的改变？ c) 先前提到的 MDMA 用户睡眠结构的改变是否会在色氨酸耗尽后加剧，m-CPP 对 MDMA 用户和对照组的睡眠是否有不同影响？ d) MDMA 使用者对缺血性疼痛或热痛的反应是否改变？他们对吗啡的镇痛反应是否改变？ e) 之前在 MDMA 使用者中观察到的冲动和敌意差异是否可以使用其他研究工具得到证实和扩展？ 通过解决这些问题，本研究将检验 MDMA 神经毒性普遍适用于人类以及毒性会产生功能性后果的假设。该项目的长期目标是更好地描述娱乐性 MDMA 使用的公共卫生风险，并利用这一独特的人群进一步阐明大脑血清素在健康和疾病中的作用。