PET Imaging MDMA Neurotoxicity

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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.