Serotonergic neurotoxic metabolites of ecstasy identified in rat brain

Douglas C. Jones, Christine Duvauchelle, Aiko Ikegami, Christopher M. Olsen, Serrine S. Lau, Rafael De La Torre, Terrence J. Monks

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

The selective serotonergic neurotoxicity of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) depends on their systemic metabolism. We have recently shown that inhibition of brain endothelial cell γ-glutamyl transpeptidase (γ-GT) potentiates the neurotoxicity of both MDMA and MDA, indicating that metabolites that are substrates for this enzyme contribute to the neurotoxicity. Consistent with this view, glutathione (GSH) and N-acetylcysteine conjugates of α-methyl dopamine (α-MeDA) are selective neurotoxicants. However, neurotoxic metabolites of MDMA or MDA have yet to be identified in brain. Using in vivo microdialysis coupled to liquid chromatography-tandem mass spectroscopy and a high-performance liquid chromatography-coulometric electrode array system, we now show that GSH and N-acetylcysteine conjugates of N-methyl-α-MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of γ-GT with acivicin increases the concentration of GSH and N-acetylcysteine conjugates of N-methyl-α-MeDA in brain dialysate, and there is a direct correlation between the concentrations of metabolites in dialysate and the extent of neurotoxicity, measured by decreases in serotonin (5-HT) and 5-hydroxyindole acetic (5-HIAA) levels. Importantly, the effects of acivicin are independent of MDMA-induced hyperthermia, since acivicin-mediated potentiation of MDMA neurotoxicity occurs in the context of acivicin-mediated decreases in body temperature. Finally, we have synthesized 5-(N-acetylcystein-S-yl)-N- methyl-α-MeDA and established that it is a relatively potent serotonergic neurotoxicant. Together, the data support the contention that MDMA-mediated serotonergic neurotoxicity is mediated by the systemic formation of GSH and N-acetylcysteine conjugates of N-methyl-α-MeDA (and α-MeDA). The mechanisms by which such metabolites access the brain and produce selective serotonergic neurotoxicity remain to be determined.

Original languageEnglish (US)
Pages (from-to)422-431
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume313
Issue number1
DOIs
StatePublished - Apr 1 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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