MDMA Neurotoxicity in Humans: Occurence & Consequences

MDMA 对人类的神经毒性：发生率

• 批准号: 7045950
• 负责人: GEORGE A RICAURTE
• 金额: $ 39.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7045950
• 关键词: 3,4 methylenedioxymethamphetamine; behavioral /social science research tag; clinical research; cognition; drug abuse; human subject; neural information processing; neural transmission; neuropharmacologic agent; neuropharmacology; neuropsychological tests; neuropsychology; neuroregulation; neurotoxicology; neurotoxins; physiologic stressor; psychological aspect of aging; psychometrics; psychopharmacology; sleep deprivation; substance abuse related behavior

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.

描述（改编自申请人摘要）： 3，4-亚甲基二氧基甲基苯丙胺（MDMA，“迷魂药”）是一种非法苯丙胺 在美国和国外越来越受欢迎的模拟。在 除了滥用的可能性，MDMA被充分证明是一种强效的， 选择性血清素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诱导的血清素的影响， 神经毒性虽然MDMA诱导的5-羟色胺的功能性后遗症 神经毒性似乎是微妙的，一些实验室已经记录 MDMA使用者的记忆和其他认知过程异常， 匹配的对照组。由于已知参与认知的神经元 过程随着老化而减少（例如，儿茶酚胺能和胆碱能 神经元），人们担心MDMA使用者可能有发展的风险， 随着年龄的增长出现临床上显著的认知异常。的总目标 这份修订后的竞争性续期申请是为了确定 和生理挑战，旨在模拟选定的功能， 老化（即，儿茶酚胺能/胆碱能功能和/或睡眠丧失 连续性）可以用于更好地检测和表征可能的有害的 MDMA神经毒性对人类认知过程的影响。的 待检验假设是MDMA诱导的脑多巴胺能损伤将 使MDMA使用者更容易患上与以下疾病相关的认知缺陷： 干扰儿茶酚胺能和胆碱能神经传递和睡眠 连续性 该项目的具体目标是：1）确定是否存在MDMA 与匹配的对照组相比，用户更容易受到干扰 儿茶酚胺合成抑制剂α-甲基-对-酪氨酸的作用 （AMPE），对认知过程的影响; V确定MDMA使用者， 匹配的对照，更容易受到破坏性的影响， 胆碱能拮抗剂东莨菪碱对认知过程的影响 无论是睡眠剥夺，一个自然的生理挑战， 已知会导致认知缺陷（这在老年人中很常见 人群），对MDMA使用者的认知产生更深远的影响 与匹配的对照相比;以及4）为了确定是否存在 MDMA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5-羟色胺的有效测量 神经毒性 拟议的研究有望提高我们对 MDMA诱导的人类5-羟色胺神经毒性的功能后果，以及 应该进一步了解大脑血清素和其他 认知神经递质系统。

项目成果

Synthesis and neurotoxicological evaluation of putative metabolites of the serotonergic neurotoxin 2-(methylamino)-1-[3,4-(methylenedioxy)phenyl] propane [(methylenedioxy)methamphetamine].

血清素神经毒素 2-(甲氨基)-1-[3,4-(亚甲二氧基)苯基]丙烷 [(亚甲二氧基)甲基苯丙胺] 的假定代谢物的合成和神经毒理学评估。

• DOI: 10.1021/tx00025a015
• 发表时间: 1992
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Zhao,ZY;CastagnoliJr,N;Ricaurte,GA;Steele,T;Martello,M
• 通讯作者: Martello,M

MDMA ("ecstasy") and panic disorder: induction by a single dose.

MDMA（“摇头丸”）和恐慌症：单剂量诱导。

• DOI: 10.1016/0006-3223(92)90185-3
• 发表时间: 1992
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: McCann,UD;Ricaurte,GA
• 通讯作者: Ricaurte,GA

Aminergic metabolites in cerebrospinal fluid of humans previously exposed to MDMA: preliminary observations.

先前接触 MDMA 的人类脑脊液中的胺能代谢物：初步观察。

• DOI: 10.1111/j.1749-6632.1990.tb16919.x
• 发表时间: 1990
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Ricaurte,GA;Finnegan,KT;Irwin,I;Langston,JW
• 通讯作者: Langston,JW

The effect of catecholamine depletion by alpha-methyl-para-tyrosine on measures of cognitive performance and sleep in abstinent MDMA users.

α-甲基-对酪氨酸消耗儿茶酚胺对戒断 MDMA 使用者认知表现和睡眠的影响。

• DOI: 10.1038/sj.npp.1301302
• 发表时间: 2007
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: McCann,UnaD;Peterson,StephenC;Ricaurte,GeorgeA
• 通讯作者: Ricaurte,GeorgeA

Reinforcing subjective effects of (+/-) 3,4-methylenedioxymethamphetamine ("ecstasy") may be separable from its neurotoxic actions: clinical evidence.

(l-) 3,4-亚甲二氧基甲基苯丙胺（“摇头丸”）的增强主观作用可能与其神经毒性作用分开：临床证据。

• 发表时间: 1993
• 期刊: Journal of clinical psychopharmacology
• 影响因子: 2.9
• 作者: McCann,UD;Ricaurte,GA
• 通讯作者: Ricaurte,GA