(+/-)3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug of abuse with documented neurotoxic activity towards brain serotonin (5-HT) neurons. Although the acute neurotoxic effects of MDMA have been well characterized, little is known about the long-term effects of MDMA on 5-HT neurons. In rodents, there is indication that 5-HT neurons recover, but the extent, pattern and duration of the recovery remain uncertain. In nonhuman primates, which tend to sustain more severe 5-HT neuronal injury than rodents, recovery is also observed, but research during the past project period suggests that the recovery is abnormal, and highly dependent on brain region. Specifically, it appears that brain regions that initially incur more severe damage, are distant from 5-HT nerve cell bodies in the raphe, or are farther from 5-HT axon bundles (e.g., dorsal neocortex), fail to recover. In contrast, brain regions that are less severely affected, are closer to the raphe, or are next to a major 5-HT axon tract (e.g., hypothalamus), tend to recover fully, often excessively. This pattern of lasting denervation of some brain regions, with reinnervation or hyperinnervation of others suggests that, under some circumstances, MDMA injury can lead to a lasting reorganization of ascending 5-HT axonal projections. The overall goal of the proposed studies is to more fully characterize these changes in 5-HT axonal projection patterns, and to probe for possible functional consequences.
The specific aims of the project are to: (1) Further characterize the altered reinnervation pattern induced by MDMA in primates; (2) Confirm and extend the preliminary observation that these axonal changes are associated with a partial loss of serotonergic nerve cell bodies in the rostral raphe nuclei of the brain stem; and (3) Identify functional consequences of MDMA-induced serotonergic neurotoxicity in nonhuman primates. A combination of quantitative autoradiographic, neurochemical, and immunohistochemical methods will be used to further characterize the altered 5-HT innervation pattern. In addition, these same methods will be used to determine if the aberrant innervation pattern is influenced by the severity of the initial MDMA injury, and if it persists longer than the 18-month post-drug survival thus far studied. The preliminary finding of 5-HT-immunoreactive nerve cell body loss will be pursued by determining whether it can be confirmed in additional MDMA-treated monkeys, and by ascertaining whether it can be substantiated with different 5-HT neuronal markers (e.g., antibody directed against tryptophan hydroxylase) and alternate methods (silver degeneration). Further, the possibility that nerve cell loss can be enhanced through use of more intense MDMA regimens will be explored. Possible functional consequences of MDMA neurotoxicity will be investigated by examining whether changes in 5-HT innervation are associated with alterations in: 1) neuroendocrine function; 2) sensitivity to the behavioral effects of serotonergic drugs; 3) acquisition of a timing task; or 4) circadian activity patterns. As before, the long-term objectives of this research are to characterize the long-term neuropathologic effects of MDMA in primates and to better define the functional role of 5-HT in the CNS.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Drug Abuse Biomedical Research Review Committee (DABR)
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Frankenheim, Jerry
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Johns Hopkins University
Schools of Medicine
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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
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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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