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Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Melanie Mueller, Jie Yuan, Anne Felim, Anne Neudörffer, Frank T. Peters, Hans H. Maurer, Una D. McCann, Martine Largeron and George A. Ricaurte
Drug Metabolism and Disposition October 2009, 37 (10) 2079-2086; DOI: https://doi.org/10.1124/dmd.109.028340
Melanie Mueller
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Jie Yuan
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Anne Felim
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Anne Neudörffer
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Frank T. Peters
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Hans H. Maurer
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Una D. McCann
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Martine Largeron
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George A. Ricaurte
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Abstract

The mechanism by which the recreational drug (±)-3,4-methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals. We also further evaluated the neurotoxic potential of 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA), an MDMA metabolite recently implicated in 5-HT neurotoxicity. Lasting serotonergic deficits correlated strongly with pharmacokinetic parameters of MDMA (Cmax and area under the concentration-time curve), more weakly with those of MDA, and not at all with those of HHMA or HMMA (total amounts of the free analytes obtained after conjugate cleavage). HHMA and HMMA could not be detected in the brains of animals with high brain MDMA concentrations and high plasma HHMA and HMMA concentrations, suggesting that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and that little or no MDMA is metabolized to HHMA or HMMA in the brain. Repeated intraparenchymal administration of 5-NAC-HHMA did not produce significant lasting serotonergic deficits in the rat brain. Taken together, these results indicate that MDMA and, possibly, MDA are more important determinants of brain 5-HT neurotoxicity in the rat than HHMA and HMMA and bring into question the role of metabolites (including 5-NAC-HHMA) in MDMA neurotoxicity.

  • MDMA, 3,4-methylenedioxymethamphetamine
  • 5-HT, serotonin
  • HHMA, 3,4-dihydroxymethamphetamine
  • HHA, 3,4-dihydroxyamphetamine
  • THMA, 2,4,5-trihydroxymethamphetamine
  • SKF-525A, 2-diethylaminoethyl 2:2-diphenylvalerate hydrochloride
  • MDA, 3,4-methylenedioxyamphetamine
  • 5-NAC-HHMA, 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine
  • HMMA, 4-hydroxy-3-methoxymethamphetamine
  • 5-HIAA, 5-hydroxyindol acetic acid
  • 5,7-DHT, 5,7-dihydroxytryptamine
  • SMBS, sodium metabisulfite
  • LC-MS, liquid chromatography-mass spectrometry
  • AUC, area under the curve
  • aCSF, artificial cerebrospinal fluid.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    • Received April 30, 2009.
    • Accepted July 21, 2009.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (10)
Drug Metabolism and Disposition
Vol. 37, Issue 10
October 2009
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Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Melanie Mueller, Jie Yuan, Anne Felim, Anne Neudörffer, Frank T. Peters, Hans H. Maurer, Una D. McCann, Martine Largeron and George A. Ricaurte
Drug Metabolism and Disposition October 1, 2009, 37 (10) 2079-2086; DOI: https://doi.org/10.1124/dmd.109.028340

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OtherArticle

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Melanie Mueller, Jie Yuan, Anne Felim, Anne Neudörffer, Frank T. Peters, Hans H. Maurer, Una D. McCann, Martine Largeron and George A. Ricaurte
Drug Metabolism and Disposition October 1, 2009, 37 (10) 2079-2086; DOI: https://doi.org/10.1124/dmd.109.028340
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