Serotonergic neurotoxic metabolites of ecstasy identified in rat brain

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

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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 2005

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N-Methyl-3,4-methylenedioxyamphetamine
acivicin
3,4-Methylenedioxyamphetamine
Brain
Acetylcysteine
Dialysis Solutions
Serotonin
Induced Hyperthermia
Hydroxyindoleacetic Acid
gamma-Glutamyltransferase
Microdialysis
Subcutaneous Injections
Body Temperature
Liquid Chromatography
Acetic Acid
Glutathione
Dopamine
Mass Spectrometry
Electrodes
Endothelial Cells

ASJC Scopus subject areas

  • Pharmacology

Cite this

Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. / Jones, Douglas C.; Duvauchelle, Christine; Ikegami, Aiko; Olsen, Christopher M.; Lau, Serrine; De La Torre, Rafael; Monks, Terrence.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 313, No. 1, 04.2005, p. 422-431.

Research output: Contribution to journalArticle

Jones, Douglas C. ; Duvauchelle, Christine ; Ikegami, Aiko ; Olsen, Christopher M. ; Lau, Serrine ; De La Torre, Rafael ; Monks, Terrence. / Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 313, No. 1. pp. 422-431.
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