MDMA is a popular recreational drug that damages serotonergic nerve terminals in the brain of rodent as well as non-human primates. Whether the damage is reversible or permanent is currently unknown, but this is an important question given recent preliminary findings indicating that humans who use MDMA may incur central serotonergic neuronal damage. The purpose of this research is to characterize the long-term effects of MDMA on serotonergic neurons in the b#in of non-human primates, and to define factors that determine whether the toxic effects of MDMA are reversible or permanent. The first set of studies will examine the potential for neuronal recovery in MDMA-treated monkeys that have sustained severe serotonergic nerve fiber damage, but no cell body loss in the raphe nuclei. Pilot studies indicate that partial recovery of serotonin takes place in these animals over a ten week period. This finding will be confirmed and extended by (1) measuring other chemical markers for serotonergic fibers (serotonin uptake sites and 5- hydroxyindoleacetic acid concentrations), (2) establishing the time-course and extent of recovery in various brain regions, (3) determining whether neurochemical recovery is related to regeneration of serotonergic nerve fibers and (4) investigating if the distribution and appearance of the regenerated fibers is normal. Results from these studies should yield information regarding the long-term effects of MDMA on central serotonergic neurons in non-human primates, and could prove directly relevant to humans who have sustained MDMA-induced neuronal damage. A second set of studies will attempt to identify conditions under which MDMA produces permanent toxic effects on central serotonergic neurons in the primate. In particular, it will be examined if higher or more protected dosage regimens of MDMA lead to destruction of serotonergic nerve cell bodies in the raphe nuclei. Under such conditions, irreversible effects would, of course, be anticipated. Identification of a dosage regimen of MDMA that produces extensive destruction of serotonergic nerve cell bodies could have several useful applications. MDMA-treated monkeys with a large and permanent depletion of brain serotonin could be used to define the functional role of serotonergic neurons in the primate brain. Studies in such animals could also provide valuable guidance for the clinical assessment of humans who show biochemical evidence of MDMA-induced serotonergic neuronal damage. The finding that higher or more protracted doses of MDMA produce irreversible effects on serotonergic neurons would also have important implications for those humans who use repeated high doses of this drug. The long-term objectives of this research are to further define the functional role of serotonergic neurons in the primate brain and to characterize the long-term consequences of MDMA intoxication in human and non-human primates.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA005707-03
Application #
3461159
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1989-03-01
Project End
1994-02-28
Budget Start
1991-03-01
Budget End
1992-02-29
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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