MDMA Neurotoxicity in Humans: Occurence & Consequences

描述(改编自申请人的摘要)： 3，4-亚甲基二氧甲基苯丙胺(MDMA，“摇头丸”)是一种非法苯丙胺 在美国和国外越来越受欢迎的模拟。在……里面 除了其滥用潜力外，MDMA还被公认为是一种强有力的 动物体内选择性5-羟色胺神经毒素。越来越多的证据表明 人类MDMA使用者也容易受到MDMA诱导的5-羟色胺的影响 神经毒性。尽管MDMA诱导的5-羟色胺的功能性后遗症 神经毒性似乎微乎其微，一些实验室已经记录在案 MDMA使用者的记忆和其他认知过程异常与 与对照组相匹配。因为已经知道神经元参与了认知 过程随着年龄的增长而减少(例如儿茶酚胺能和胆碱能 神经元)，人们担心使用MDMA的人可能会患上 随着年龄的增长，临床上显著的认知异常。的总目标是 这项修订后的竞争性续签申请是为了确定药理学上是否 和生理挑战，旨在模拟选定的特征 衰老(即儿茶酚胺/胆碱能功能丧失和/或睡眠 连续性)可以用来更好地检测和表征可能有害的 MDMA神经毒性对人类认知过程的影响。这个 有待检验的假设是，MDMA诱导的脑5-羟色胺能损伤将 使MDMA使用者更容易出现与以下各项相关的认知缺陷 儿茶酚胺能和胆碱能神经传递障碍与睡眠 连续性。 该项目的具体目标是：1)确定MDMA是否 与匹配的对照组相比，用户更容易受到破坏性因素的影响 儿茶酚胺合成抑制剂α-甲基对酪氨酸的作用 (Ampe)，关于认知过程；V，以确定MDMA用户是否与 相匹配的对照，更容易受到 胆碱能拮抗剂东莨菪碱对认知过程的影响；3)测定 不管是不是睡眠剥夺，这是一个自然主义的生理挑战 已知会导致认知障碍(这在老年人中很常见 人群)，对MDMA使用者的认知产生更深刻的影响 与匹配的对照组进行比较；以及4)确定是否存在 摇头丸使用者认知功能障碍与脑脊液水平的关系 5-羟基吲哚乙酸--MDMA诱导的脑内5-羟色胺的有效方法 神经毒性。 拟议的研究有望增进我们对 MDMA诱导的人类5-羟色胺神经毒性的功能后果，以及 应该促进对大脑5-羟色胺和其他 认知中的神经递质系统。

DESCRIPTION (Adapted from applicant's abstract): The 3,4-Methylene-dioxymethamphetamine (MDMA, 'Ecstasy'') is an illicit amphetamine analog that is increasing in popularity in the United States and abroad. In addition to its abuse potential, MDMA is well documented as a potent and selective serotonin neurotoxin in animals. A growing body of evidence indicates that human MDMA users are also susceptible to MDMA-induced serotonin neurotoxicity. Although functional sequelae of MDMA-induced serotonin neurotoxicity appear to be subtle, a number of laboratories have documented abnormalities in memory and other cognitive processes in MDMA users compared to matched control groups. Since it is known that neurons involved in cognitive processes decrease with aging (e.g., catecholaminergic and cholinergic neurons), there is concern that MDMA users may be at risk for developing clinically significant cognitive abnormalities as they age. The overall goal of this revised competing renewal application is to determine if pharmacological and physiological challenges that are intended to simulate selected features of aging (i.e., loss of catecholaminergic/cholinergic function and/or sleep continuity) can be used to better detect and characterize possible detrimental effects of MDMA neurotoxicity upon cognitive processes in humans. The hypothesis to be tested is that MDMA-induced brain serotonergic injury will render MDMA users more susceptible to cognitive deficits associated with disruption of catecholaminergic and cholinergic neurotransmission and sleep continuity. The Specific Aims of the project are: 1) To determine whether or not MDMA users, compared to matched controls, are more susceptible to the disruptive effects of the catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine (AMPE), on cognitive processes; V To determine if MDMA users, compared to matched controls, are more susceptible to the disruptive effects of the cholinergic antagonist, scopolamine, on cognitive processes; 3) To determine whether or not sleep deprivation, a naturalistic physiological challenge that is known to lead to deficits in cognition (and which is common in elderly populations), produces more profound effects on cognition in MDMA users compared to matched controls; and 4) To determine whether there is a relationship between cognitive deficits in MDMA users and the level of CSF 5-hydroxyindoleacetic acid, a validated measure of MDMA-induced brain serotonin neurotoxicity. The proposed studies hold promise for improving our understanding of the functional consequences of MDMA-induced serotonin neurotoxicity in humans, and should advance knowledge regarding the role of brain serotonin and other neurotransmitter systems in cognition.