PET Imaging MDMA Neurotoxicity

描述(申请人提供)：(+)3，4-亚甲基二氧基甲基苯丙胺(MDMA，“摇头丸”)，一种广受欢迎的娱乐药物，是一种在实验动物中有效的脑5-羟色胺(5-HT)神经毒素。越来越多的证据表明，MDMA也会对人类的大脑产生5-羟色胺的神经毒性作用。然而，需要更多的数据才能有信心地得出这一结论。流行的观点认为，MDMA是一种选择性的5-羟色胺神经毒素，因为在用MDMA治疗的动物中，多巴胺(DA)和去甲肾上腺素神经元通常不受影响。然而，最近我们发现，用MDMA剂量方案治疗的猴子和狒狒，除了显著的5-羟色胺神经毒性外，还会出现严重的DA神经毒性，这种剂量方案与娱乐MDMA使用者经常使用的MDMA方案非常相似。这一意想不到的发现提出了一种可能性，即除了5-羟色胺神经损伤外，一些MDMA使用者可能遭受严重的DA神经损伤。建议的PET成像研究的总体目标是更好地表征MDMA对人脑的长期影响。 这种相互竞争的更新应用程序的目的是：1)确认和扩展先前的PET成像数据，这些数据表明戒酒的MDMA使用者大脑5-羟色胺转运体(SERT)的密度持续下降；2)确定先前在几个小时内服用多剂量MDMA的个体是否像最近在非人类灵长类动物中发现的那样，出现纹状体DA转运体(DAT)和囊泡单胺转运体(VMATs)的显著减少；3)确定戒毒MDMA使用者是否在基线或静脉注射混合5-羟色胺激动剂和释放剂m-氯苯基哌嗪(m-CPP)后显示局部脑葡萄糖利用(RCMRglu)改变的证据。 长远来说，拟议的研究旨在确定在青年时期滥用MDMA的个人是否在不知不觉中导致脑多巴胺/5-羟色胺神经毒性，从而增加他们在以后的生活中患上与脑多巴胺和/或5-羟色胺缺乏有关的神经精神障碍的风险(例如，痴呆症、帕金森症、抑郁/焦虑)。此外，拟议的18FDG研究将解决以下问题：接触MDMA是否会导致最基本水平的大脑功能改变，即葡萄糖利用。

DESCRIPTION (provided by applicant): (+)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), a popular recreational drug, is a potent brain serotonin (5-HT) neurotoxin in experimental animals. There is growing evidence that MDMA also produces brain 5-HT neurotoxic effects in humans. However, additional data are needed to reach this conclusion with confidence. The prevailing view is that MDMA is a selective 5-HT neurotoxin, since in animals treated with MDMA, dopamine (DA) and norepinephrine neurons are typically unaffected. Recently, however, we have found that monkeys and baboons treated with a dosage regimen of MDMA modeled closely after one often used by recreational MDMA users develop profound DA neurotoxicity, in addition to significant 5-HT neurotoxicity. This unexpected finding raises the possibility that, in addition to 5-HT neural injury, some MDMA users may sustain significant DA neural injury. The overall goal of the proposed PET imaging studies is to better characterize the long-term effects of MDMA on the human brain. The aims of this competing renewal application are: 1) To confirm and extend previous PET imaging data indicating that abstinent MDMA users have lasting reductions in the density of brain 5-HT transporters (SERTs); 2) To determine if individuals who have previously taken multiple doses of MDMA over several hours ("bingers '') develop profound reductions in striatal DA transporters (DATs) and vesicular monoamine transporters (VMATs) similar to those recently discovered in nonhuman primates; 3) To determine if abstinent MDMA users show evidence of altered regional cerebral glucose utilization (rCMRglu), either at baseline,or after intravenous infusion of the mixed 5-HT agonist and releaser, m-chlorophenylpiperazine (m-CPP). In the long-term, the proposed studies are intended to determine if individuals who abuse MDMA in their youth are, unwittingly, incurring brain DA/5-HT neurotoxicity, thereby increasing their risk of developing neuropsychiatric disorders related to brain DA and/or 5-HT deficiency later in life (e.g., dementia, Parkinsonism, depression/anxiety). In addition, the proposed 18FDG studies will address the question of if MDMA exposure leads to altered brain function at the most fundamental level, glucose utilization.