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资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。 3,4-甲基二甲基甲基苯丙胺（MDMA）是人类休闲使用的合成苯丙胺衍生物。尽管具有非法的地位，并且知道MDMA对动物的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。该项目的目的是双重的：1）确认并扩展数据，表明娱乐性MDMA使用者会损害中央5-羟色胺神经元； 2）进一步探测MDMA暴露的功能后果。特别是，将在受控的住院环境中进行生化和诱导研究，以解决以下特定问题：1）生化研究：a）使用单胺代谢物的CSF测量值，可以确定：（i）MDMA神经毒性是否剂量（暴露）是相关的； （ii）对MDMA神经毒性的反应是否存在性别差异； （iii）在接触最大的MDMA用户中，CSF HVA是否也减少了。 b）使用神经内分泌挑战与M-CPP，可以检测到MDMA诱导的脑血清素神经神经的改变（即，催乳素和/或皮质醇反应是否改变了？）。 2）功能研究：a）MDMA使用者是否改变了对药理学（M-CPP）挑战的情绪，焦虑，温度或认知反应？ b）可以在MDMA使用者中检测到情绪，焦虑和认知（推定涉及5-羟色胺）的情绪，焦虑和认知（行为领域），以应对物理化学挑战（色氨酸耗竭）？ c）在色氨酸耗竭后，MDMA用户中先前注意到的睡眠体系结构的变化是否加剧了，并且M-CPP是否会差异地影响MDMA用户和控件中的睡眠？ d）MDMA使用者对缺血性或热疼痛的反应改变了吗？他们对吗啡的镇痛反应是否改变了？ e）使用其他研究工具确认并扩展了先前在MDMA使用者中观察到的冲动和敌意的差异？ 通过解决这些问题，这项研究将检验以下假设：MDMA神经毒性向人类推广，并且毒性具有功能后果。该项目的长期目标是更好地描述公共卫生的娱乐性MDMA使用，并利用这一独特的个体人群进一步阐明脑血清素在健康和疾病中的作用。