BEHAVIORAL TOXICITY OF MDMA IN RHESUS MONKEYS

MDMA 对恒河猴的行为毒性

• 批准号: 6923095
• 负责人: MICHAEL A. TAFFE
• 金额: $ 41.83万
• 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/6923095
• 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）：近几十年来，（+/-）3,4-亚甲二氧基甲基苯丙胺（MDMA，“摇头丸”）的娱乐用途越来越流行。美国的主要调查报告显示，摇头丸的使用率急剧上升，而其他一些娱乐性药物的使用率则保持稳定或下降。大学生的终生患病率为 12-18%，因此很大一部分人口接触 MDMA。大量研究表明，戒除 MDMA 的人在一系列认知任务上表现出缺陷。过去几十年对非人类灵长类动物模型的研究表明，高剂量的 MDMA（10 毫克/千克）；当连续 4 天以 12 小时的间隔给药时，可选择性地减少许多大脑区域的血清素 (5-HT) 轴突和末梢标记。然而，这种 MDMA 相关的 5-HT 神经毒性不足以在未受挑战的条件下使猴子产生认知或运动改变。然而，先前的猴子模型并未采用类似于人类使用者的重复、间歇性给药模式。为了研究 MDMA 人类使用者的认知和运动障碍是由 5HT 轴突修剪/再神经支配的重复循环引起的新假设，将在恒河猴中根据以下目标进行实验。具体目标 I：确定重复、间歇性接触低剂量 MDMA 是否会导致可检测到的神经化学、行为或电生理学改变。具体目标 II：确定短间隔、多剂量暴露于低剂量 MDMA（“MDMA 叠加”）是否会产生与重复、高剂量、长间隔产生的神经化学、行为和电生理学特征相似的结果产生血清素神经毒性的治疗方案。具体目标 III：确定反复接触 MDMA 是否会导致进行性电生理学、神经化学或时间生理学紊乱。具体目标 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表现。