PET Imaging MDMA Neurotoxicity

（+）3,4-亚甲基二氧基甲基苯丙胺（MDMA，“摇头丸”）是一种流行的娱乐性药物，在实验动物中是一种有效的脑血清素（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-羟色胺神经毒性作用。然而，需要更多的数据才能有把握地得出这个结论。普遍的观点是MDMA是一种选择性的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，猴子和狒狒在使用与娱乐性MDMA使用者经常使用的MDMA剂量方案密切相关的MDMA剂量方案后，除了显著的5-HT神经毒性外，还出现了严重的DA神经毒性。这一意想不到的发现提出了一种可能性，即除了5-HT神经损伤外，一些MDMA使用者可能会遭受严重的DA神经损伤。提议的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。

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.