Determinants of transition states in MDMA self-administration

描述（由申请方提供）：流行病学报告显示，（1）3，4-亚甲二氧基甲基苯丙胺（MDMA，“摇头丸”）继续被大部分年轻人使用。研究进一步表明，多达40%的使用者至少暂时依赖于MDMA，有经验的使用者滥用一系列其他物质，并且可能每周甚至每天多次滥用MDMA。也有人知道，一些Ecketone使用者表现出持久的认知和情绪变化，甚至在停止Ecketone使用数年后。然而，与安非他明和甲基安非他明等结构上相关的药物相比，动物研究的最低限度一直致力于了解二亚甲基双氧安非他明重复自我给药的决定因素。初步研究表明，与其他精神兴奋剂相比，MDMA似乎是一种较弱的兴奋剂，因此需要对造成频繁或强迫使用MDMA的因素进行进一步研究。MDMA自身给药的差异与MDMA的多巴胺能激动剂特性增加有关的假设得到了先前观察结果的支持，即增加多巴胺能张力的药物可能会减少精神兴奋剂的自身给药。这类工作不仅将有助于了解二亚甲基双氧安非他明/摇头丸滥用的发展情况，而且可能有助于了解影响接触其他精神兴奋剂的少数人中哪些人最终过渡到依赖性的因素。拟定的研究将使用大鼠静脉自我给药模型来检测可能导致从偶然性兴奋过度到强迫性兴奋过度的因素。这些实验将首先检查方法学变量，如训练剂量、给药途径和进入期的持续时间，这些变量尚未针对MDMA自我给药进行系统处理。其他研究将检查旨在模拟人类使用者环境的情境因素（如高环境温度和高热、转轮活动和暴露于可消耗阿托宁的高剂量MDMA方案），这些因素可能促进向依赖性的转变。 公共卫生相关性：大约15- 20%的年轻人使用过娱乐性药物3，4-亚甲二氧基-甲基苯丙胺（MDMA，称为“Ecketamine”），其中许多使用者在使用Ecketamine时变得依赖;临床上显著的抑郁和焦虑症状，以及认知能力差在停止Ecketamine使用后可能持续数年。此外，在美国，每年约有8，500人在使用Eccinate后出现严重的高热、癫痫发作和其他需要紧急医疗干预的医学症状。拟议的研究旨在确定可能增加这种娱乐性药物的使用和/或促进从偶然使用过渡到依赖的情境和神经化学因素。

DESCRIPTION (provided by applicant): Epidemiological reports show that (1)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") continues to be used by large fractions of young adults. Studies have further suggested that up to 40 percent of users become at least temporarily dependent on MDMA, experienced users abuse an array of other substances and may abuse MDMA several times per week or even daily. It is also known that some Ecstasy users exhibit lasting cognitive and mood alterations, even years after discontinuing Ecstasy use. Nevertheless, in comparison with structurally related drugs such as amphetamine and methamphetamine minimal animal research has been devoted to understanding the determinants of repeated MDMA self-administration. Initial work has shown that MDMA appears to be a weak reinforcer compared with other psychomotor stimulants, thus additional study of factors which create a transition to frequent or compulsive MDMA use is needed. The hypothesis that differences in the self administration of MDMA are related to the increased serotonergic agonist properties of MDMA is supported by prior observations that drugs which increase serotonergic tone may decrease self- administration of psychomotor stimulants. Such work will not only contribute to understanding the development of MDMA/Ecstasy abuse but may generalize to understanding factors which influence which of a minority of individuals exposed to other psychomotor stimulants will eventually transition to dependence. The proposed studies will use rat intravenous self-administration models to test factors which may underlie a transition from casual to compulsive Ecstasy use. The experiments will first examine methodological variables such as training dose, route of administration and duration of access session that have not been systematically addressed for MDMA self-administration. Additional studies will examine situational factors intended to model the human user milieu (such as high ambient temperature and hyperthermia, running wheel activity and exposure to a serotonin-depleting high dose regimen of MDMA) which may facilitate a transition to dependence. PUBLIC HEALTH RELEVANCE: Approximately 15-20 percent of young adults have used the recreational drug 3,4-methylenedioxy- methamphetamine (MDMA, known as "Ecstasy") and many of these users become dependent on Ecstasy while using; clinically significant symptoms of depression and anxiety, and poor cognitive performance can persist years after discontinuing Ecstasy use. Furthermore, in the US about 8,500 individuals per year have critical hyperthermia, seizure and other medical symptoms requiring emergency medical intervention after Ecstasy use. The proposed studies seek to determine situational and neurochemical factors which may increase use of this recreational drug and/or facilitate a transition from casual use to dependence.