PET Imaging MDMA Neurotoxicity

描述（由申请人提供）： （+）3，4-亚甲二氧基甲基苯丙胺（MDMA，“摇头丸”）是一种流行的娱乐性药物，在实验动物中是一种强效的脑5-羟色胺（5-HT）神经毒素。越来越多的证据表明，MDMA也会对人类大脑产生5-HT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。主流观点认为，MDMA是一种选择性5-HT神经毒素，因为在接受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，除了显著的5-HT神经毒性外，用MDMA给药方案治疗的猴子和狒狒（与娱乐性MDMA使用者经常使用的剂量方案密切相关）还产生了严重的DA神经毒性。这一意外的发现提出了一种可能性，即除了5-HT神经损伤外，一些MDMA使用者可能会遭受显著的DA神经损伤。拟议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。 这一竞争性更新申请的目的是：1）确认和扩展先前的PET成像数据，这些数据表明，戒断的MDMA使用者的大脑5-HT转运蛋白（SERT）密度持续降低; 2）确定以前在几个小时内多次服用MDMA的人（“暴食者”）纹状体DA转运蛋白（DAT）和囊泡单胺转运蛋白（VMAT）的显著减少，类似于最近在非人灵长类动物中发现的那些; 3）确定戒断的MDMA使用者是否在基线时或在静脉输注混合5-HT激动剂和间氯苯基哌嗪（m-CPP）后显示局部脑葡萄糖利用（rCMRglu）改变的证据。 从长远来看，拟议的研究旨在确定年轻时滥用MDMA的个人是否在无意中引起脑DA/5-HT神经毒性，从而增加他们在以后的生活中发展与脑DA和/或5-HT缺乏相关的神经精神疾病的风险（例如，痴呆、帕金森综合征、抑郁/焦虑）。此外，拟议的18 FDG研究将解决MDMA暴露是否会导致最基本水平的大脑功能改变的问题，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.