BEHAVIORAL TOXICITY OF MDMA IN RHESUS MONKEYS

MDMA 对恒河猴的行为毒性

• 批准号: 7028961
• 负责人: MICHAEL A. TAFFE
• 金额: $ 40.84万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028961
• 关键词: 3,4 methylenedioxymethamphetamine; Macaca mulatta; behavioral /social science research tag; drug abuse; electrophysiology; neurochemistry; neuropsychological tests; neurotoxicology; pathologic process; psychomotor function; serotonin; substance abuse related behavior

DESCRIPTION (provided by applicant): Recreational use of (+/-) 3,4 -methylenedioxymethamphetamine (MDMA, "Ecstasy") has become increasingly popular in recent decades. Major surveys in the US report steep increases in the rate of MDMA use while use of a number of other recreational drugs has been stable or in decline. College age adults have lifetime prevalence rates of 12-18% thus a substantial fraction of the population is exposed to MDMA. Numerous studies have shown that abstinent MDMA users exhibit deficits on a range of cognitive tasks. Work in nonhuman primate models over past decades has shown that high doses of MDMA (10 mg/kg); when administered at 12 hr intervals for 4 days, selectively reduce markers for serotonin (5-HT) axons and terminals in many brain regions. However, such MDMA-associated 5-HT neurotoxicity is not sufficient to produce cognitive or motor alterations in monkeys under unchallenged conditions. Prior monkey models have not employed repeated, intermittent dosing patterns similar to human users, however. To investigate the novel hypothesis that cognitive and motor disturbances in human users of MDMA result from repeated cycles of 5HT axon pruning/reinnervation, experiments will be conducted in rhesus macaques under the following Aims. Specific Aim I: To determine if repeated, intermittent exposure to a low dose of MDMA results in detectable neurochemical, behavioral or electrophysiological alterations. Specific Aim II: To determine if a short-interval, multi-dose exposure to low doses of MDMA ("MDMA stacking") results in a neurochemical, behavioral and electrophysiological profile similar to that produced by the repeated, high-dose, long interval regimen that produces serotonin neurotoxicity. Specific Aim III: To determine if repeated episodes of exposure to MDMA result in progressive electrophysiological, neurochemical or chronophysiological disturbance. Specific Aim IV: To determine if a history of MDMA exposure impairs acquisition and performance of a battery of neuropsychological tests.

描述（由申请人提供）：（+/-）3,4-甲基二甲基甲基苯丙胺（MDMA，“摇头丸”）的娱乐使用越来越流行。美国的重大调查报告说，使用MDMA的使用率急剧提高，而使用许多其他休闲药的使用率稳定或下降。大学年龄成年人的终身患病率为12-18％，因此大部分人口暴露于MDMA。大量研究表明，禁忌的MDMA使用者在一系列认知任务上表现出赤字。过去几十年来，非人类灵长类动物模型的工作表明，高剂量的MDMA（10 mg/kg）；当以12个小时的间隔给药4天时，在许多大脑区域中有选择地减少5-羟色胺（5-HT）轴突和末端的标记。但是，这种与MDMA相关的5-HT神经毒性不足以在不受挑战的条件下在猴子中产生认知或运动的改变。然而，先前的猴子模型尚未使用与人类用户相似的重复，间歇性的给药模式。为了调查新的假设，即MDMA的人使用的认知和运动障碍是由5HT轴突修剪/重新支配的反复循环引起的，将在以下目标下在恒河猕猴中进行实验。特定目的I：确定是否重复，间歇性接触低剂量的MDMA会导致可检测到的神经化学，行为或电生理学改变。具体目的II：确定短剂量的多剂量暴露于低剂量的MDMA（“ MDMA堆叠”）是否导致神经化学，行为和电生理学特征类似于由重复的，高剂量的，长的间隔方案产生的，从而产生羟色胺神经毒性。特定的目标III：确定在进行性电生理，神经化学或年流生理学障碍的进行性电生理学中，是否重复暴露于MDMA。特定目的IV：确定MDMA暴露史是否会损害一系列神经心理学测试的获取和性能。