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TOXICOLOGY

Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain

Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas (D.C.J., C.D., A.I., C.M.O.); Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, Arizona (S.S.L., T.J.M.); and Pharmacology Research Unit, Institut Municipal d'Investigació Mèdica, Barcelona, Spain (R.d.l.T.)

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 -glutamyl transpeptidase (-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 -methyl dopamine (-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--MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of -GT with acivicin increases the concentration of GSH and N-acetylcysteine conjugates of N-methyl--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--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--MeDA (and -MeDA). The mechanisms by which such metabolites access the brain and produce selective serotonergic neurotoxicity remain to be determined.

Address correspondence to: Dr. Terrence J. Monks, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, 1703, E. Mabel Street, Tucson, AZ 85721-0207. E-mail: scouser{at}pharmacy.arizona.edu

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