Maternal MDMA (Ecstasy) Exposure and Fetal Physiology

这项R21探索/发展赠款的目标是量化母亲摇头丸(亚甲二氧基甲基苯丙胺；MDMA)消费对胎儿大脑和全身的影响。即使其他非法药物的使用量减少(或至少保持不变)，内源性甲基苯丙胺衍生物MDMA的受欢迎程度仍在继续增加。这一趋势在青少年和青壮年人群中尤为明显。与这一应用特别相关的是，报告的育龄妇女和实际怀孕妇女的消耗率上升。来自人类和动物的各种研究结果表明，怀孕期间接触MDMA会损害胎儿，虽然已有几个过程与这些行为异常的产生有关，但胎儿对母亲接触MDMA的实际反应尚不清楚。这项提议的目的是利用宫内技术(例如，近红外光谱和胎儿微透析)与更标准的监测技术相结合，以确定胎儿对母亲接触MDMA的急性反应。实验目标：1.确定母亲接触MDMA对胎儿脑氧合、胎儿多巴胺能和5-羟色胺能神经传递的影响，以及胎儿(和母体)心血管功能、体温、动脉血气状态和神经内分泌因子的影响；2.将生理变化与胎儿中枢神经系统和胎儿/母亲血液中MDMA水平的变化联系起来；3、评估母亲接触MDMA后的早产和近期脑组织病理学改变，并将胎儿神经元损伤的严重程度(和类型)与观察到的生理变化相关联。实验将比较MDMA对注入盐水的动物的影响。模仿与一些已报道的人类剂量模式一致的方案，每只母羊每隔3小时给每只母羊注射2 mg/kg的MDMA，总剂量为6 mg/kg。胎儿和产妇的反应将在最后一次服药后12小时内进行监测。实验目标的实现将产生大量关于MDMA对胎儿影响的新信息。这些信息将引起MDMA研究人员、临床医生和药物滥用工作者的兴趣，因为我们预计这项研究将有助于阐明怀孕期间服用MDMA的健康风险。

The goal of this R21 Exploratory/Development grant is to quantify the fetal cerebral and systemic effects of maternal ecstasy (methylenedioxymethamphetamine; MDMA) consumption. The popularity of the entactogenic methamphetamine derivative MDMA continues to increase even as the use of other illicit drugs decreases (or at least remain constant). This MDMA trend is particularly noticeable in adolescent and young adult populations. Of specific relevance to this application is the elevated incidence of reported consumption by women of child-bearing age and by those who are actually pregnant. Results from various human and animal studies indicate that exposure to MDMA during pregnancy can harm the fetus and while several processes have been implicated in producing these behavioral anomalies the actual responses of the fetus to maternal MDMA exposure are not known. The purpose of this proposal is to utilize in utero technologies (e.g. near-infrared spectroscopy and fetal microdialysis) in combination with more standard monitoring techniques to determine the acute fetal responses to maternal MDMA exposure. Experimental Goals: 1. To determine the effects of maternal MDMA exposure on fetal cerebral oxygenation, fetal dopaminergic and serotonergic neurotransmission, and fetal (and maternal) cardiovascular function, body temperature, arterial blood gas status, and neuroendocrine factors; 2. To relate the physiologic changes to changes in fetal CNS and fetal/maternal blood levels of MDMA; 3, To assess preterm and nearterm brain histopathology following maternal MDMA exposure and to correlate the severity (and type) of fetal neuronal injury with the observed physiologic changes. Experiments will compare the effects of MDMA exposure to saline-infused animals. Mimicking a regimen that is consistent with some reported human dosage patterns, 2 mg/kg treatments of MDMA will be thrice administered to each ewe at 3 h intervals for a total dose of 6 mg/kg. The fetal and maternal responses will monitored up to 12 h after the last dose. Achievement of the experimental goals will yield a significant amount of new information regarding the effects of MDMA upon the fetus. Such information will be of interest to MDMA researchers, clinicians, and substance-abuse workers as we anticipate that this research will help elucidate the health risks of MDMA consumption during pregnancy.