(+) 3, 4-methylenedioxvmethamphetamine (MDMA, """"""""Ecstasy"""""""") is a potent serotonin (5-HT) neurotoxin in animals, and growing evidence indicates that MDMA also produces 5-HT neurotoxic effects in humans. Although functional sequelae of MDMA neurotoxicity remain largely unknown, a number of investigators have recently documented abnormalities in cognitive function in MDMA users. Until now, the prevailing view has been that MDMA is a highly selective 5-HT neurotoxin and that cognitive deficits in MDMA users are likely to be related to brain 5-HT injury. However, we have recently found that when MDMA is given to nonhuman primates according to a dosing schedule that closely simulates the use of MDMA by many humans, brain dopamine (DA) neurons are also severely affected. This unexpected preliminary finding raises the possibility that some, or all, of the cognitive impairments noted in human MDMA users may be related to DA or combined DA/5-HT deficiency, rather than 5-HT deficiency. It also raises the possibility that the difficulty in documenting cognitive deficits in MDMA-treated monkeys has been related to that fact that, until now, only monkeys treated with regimens of MDMA that produce selective 5-HT lesions have been evaluated. The overall goal of this competing renewal application is to further characterize MDMA-induced DA neurotoxicity in monkeys, and to explore the potential relation between combined DA/5-HT lesions and alterations in cognitive and/or motor function in MDMA-treated primates.
The specific aims of the project are: 1) To confirm and extend recent preliminary findings demonstrating that a dosage regimen of MDMA that closely parallels that used by many humans produces severe DA neurotoxic effects in nonhuman primates, in addition to anticipated 5-HT neurotoxic changes; 2) To determine if squirrel monkeys with MDMA-induced 5-HT/DA lesions demonstrate memory deficits analogous to those seen in human MDMA users; and 3) To determine if monkeys treated with a regimen of MDMA that also damages brain DA neurons are at increased risk for developing a Parkinsonian syndrome following administration of the catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine (AMPT). The long-range goal of the proposed studies is to better understand the long-term effects of MDMA on the primate central nervous system (CNS), with the expectation that such knowledge will provide a framework for reliably interpreting, anticipating and, possibly, treating potential deleterious effects of MDMA in humans.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
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Frankenheim, Jerry
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Goodwin, Amy K; Mueller, Melanie; Shell, Courtney D et al. (2013) Behavioral effects and pharmacokinetics of (±)-3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) after intragastric administration to baboons. J Pharmacol Exp Ther 345:342-53
Mueller, Melanie; Maldonado-Adrian, Concepcion; Yuan, Jie et al. (2013) Studies of (ýý)-3,4-methylenedioxymethamphetamine (MDMA) metabolism and disposition in rats and mice: relationship to neuroprotection and neurotoxicity profile. J Pharmacol Exp Ther 344:479-88
Mueller, Melanie; Yuan, Jie; McCann, Una D et al. (2013) Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations. Int J Neuropsychopharmacol 16:791-801
Mueller, Melanie; Yuan, Jie; Maldonado Adrian, Concepcion et al. (2011) Inhibition of 3,4-methylenedioxymethamphetamine metabolism leads to marked decrease in 3,4-dihydroxymethamphetamine formation but no change in serotonin neurotoxicity: implications for mechanisms of neurotoxicity. Synapse 65:983-90
Neudorffer, Anne; Mueller, Melanie; Martinez, Claire-Marie et al. (2011) Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6-(N-acetylcystein-S-yl) conjugate. Chem Res Toxicol 24:968-78
Mueller, Melanie; Goodwin, Amy K; Ator, Nancy A et al. (2011) Metabolism and disposition of 3,4-methylenedioxymethamphetamine (""ecstasy"") in baboons after oral administration: comparison with humans reveals marked differences. J Pharmacol Exp Ther 338:310-7
Mueller, Melanie; Kolbrich-Spargo, Erin A; Peters, Frank T et al. (2009) Hydrolysis of 3,4-methylenedioxymethamphetamine (MDMA) metabolite conjugates in human, squirrel monkey, and rat plasma. Anal Bioanal Chem 393:1607-17
Mueller, Melanie; Peters, Frank T; Huestis, Marilyn A et al. (2009) Simultaneous liquid chromatographic-electrospray ionization mass spectrometric quantification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its metabolites 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxymethamphetamine and 3,4-methylenedioxya Forensic Sci Int 184:64-8
Mueller, Melanie; Yuan, Jie; Felim, Anne et al. (2009) Further studies on the role of metabolites in (+/-)-3,4-methylenedioxymethamphetamine-induced serotonergic neurotoxicity. Drug Metab Dispos 37:2079-86
Mueller, Melanie; Kolbrich, Erin A; Peters, Frank T et al. (2009) Direct comparison of (+/-) 3,4-methylenedioxymethamphetamine (""ecstasy"") disposition and metabolism in squirrel monkeys and humans. Ther Drug Monit 31:367-73

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