Determinants of transition states in MDMA self-administration

MDMA 自我给药过渡态的决定因素

• 批准号: 8580927
• 负责人: MICHAEL A. TAFFE
• 金额: $ 37.98万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580927
• 关键词: Acute; Address; Age; Amphetamines; Animal Experimentation; Anxiety; Attenuated; Attitude; Behavioral; Body Temperature; Brain; Cercopithecidae; Chronic; Clinical; Cocaine; Cognitive; Data; Dependence; Development; Dose; Drug abuse; Emergency Situation; Epidemiology; Etiology; Exercise; Exhibits; Exposure to; Future; Goals; Heroin; High Prevalence; Human; Hyperthermia; Ice; Individual; Intervention; Intravenous; Literature; Maintenance; Medical; Methamphetamine; Minority; Modeling; Monitor; Motor Activity; Neuraxis; Perception; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phase I Clinical Trials; Physiologic Thermoregulation; Physiological; Prevalence; Property; Psychotherapy; Rattus; Regimen; Reporting; Risk; Rodent; Rodent Model; Role; Route; Running; Safety; Schedule; Seizures; Self Administration; Serotonin; Serotonin Agonists; Signal Transduction; Students; Surveys; Symptoms; Techniques; Temperature; Testing; Time; Training; Work; base; clinically significant; cohort; depressive symptoms; design; disturbance in affect; ecstasy; ecstasy abuse; experience; innovation; interest; neurochemistry; neurotoxicity; news; novel therapeutics; pre-clinical research; preclinical study; public health relevance; recreational drug use; reinforcer; research study; young adult

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.

描述（由申请人提供）：流行病学报告表明，（1）3,4-甲基二甲基甲基苯丙胺（MDMA，“摇头丸”）继续被大的年轻人分数使用。研究进一步表明，多达40％的用户至少暂时依赖MDMA，经验丰富的用户滥用其他物质，可能每周甚至每天滥用MDMA几次。众所周知，即使在停止狂喜使用后的几年，一些狂喜用户也表现出持久的认知和情绪改变。然而，与结构相关的药物（如苯丙胺和甲基苯丙胺最小动物研究）相比，已经致力于理解重复的MDMA自我给药的决定因素。最初的工作表明，与其他精神运动兴奋剂相比，MDMA似乎是一种弱的增强剂，因此需要对导致过渡到频繁或强迫性MDMA使用的因素进行的进一步研究。先前的观察结果支持了MDMA自我给药的差异与MDMA的血清素能激动剂特性的增加有关的假设，即提高血清素能张力张力的药物可能会降低心理体兴奋剂的自我施用。这样的工作不仅有助于理解MDMA/摇头丸滥用的发展，而且可能会概括地了解影响少数人受到其他精神运动兴奋剂的少数人最终将过渡到依赖的因素。拟议的研究将使用大鼠静脉自我给药模型来测试可能是从休闲到强迫性狂喜使用的过渡的因素。实验将首先检查方法学变量，例如训练剂量，给药途径和访问持续时间，这些变量尚未系统地解决MDMA自我管理。其他研究将检查旨在对人类用户环境建模的情况因素（例如高环境温度和高温，跑步轮活动以及暴露于5-羟色胺耗尽MDMA的高剂量方案），这可能会促进依赖的过渡。 公共卫生相关性：大约15-20％的年轻人使用了3,4-甲基二甲基甲基苯丙胺（MDMA，称为“狂喜”）的休闲药物，其中许多使用者在使用时依赖摇头丸；临床上显着的抑郁和焦虑症状以及停用摇头丸的使用后，可能会持续数年的认知表现。此外，在美国，每年约有8500名个人患有关键的高温，癫痫发作和其他医疗症状，需要摇头丸后紧急医疗干预。拟议的研究旨在确定可能增加这种娱乐性药物使用和/或促进从随意使用到依赖性的过渡的情况和神经化学因素。