Faculty Collaboration Database

Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. J Pharmacol Exp Ther 2005 Apr;313(1):422-31

Date

01/07/2005

Pubmed ID

15634943

DOI

10.1124/jpet.104.077628

Scopus ID

2-s2.0-15744365687 (requires institutional sign-in at Scopus site)   108 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 gamma-glutamyl transpeptidase (gamma-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 alpha-methyl dopamine (alpha-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-alpha-MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of gamma-GT with acivicin increases the concentration of GSH and N-acetylcysteine conjugates of N-methyl-alpha-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-alpha-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-alpha-MeDA (and alpha-MeDA). The mechanisms by which such metabolites access the brain and produce selective serotonergic neurotoxicity remain to be determined.

Author List

Jones DC, Duvauchelle C, Ikegami A, Olsen CM, Lau SS, de la Torre R, Monks TJ

Author

Christopher M. Olsen PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetylcysteine
Animals
Biotransformation
Brain
Calibration
Chromatography, High Pressure Liquid
Electrodes, Implanted
Glutathione
Hypothermia
Injections, Subcutaneous
Male
Mass Spectrometry
Microdialysis
N-Methyl-3,4-methylenedioxyamphetamine
Neurotoxins
Rats
Rats, Sprague-Dawley
Serotonin
Serotonin Agents