Serotonergic neurotoxic metabolites of ecstasy identified in rat brain.
Douglas C. Jones, Christine L. Duvauchelle, Aiko Ikegami, Christopher M Olsen, Serrine S. Lau, Rafael de la Torre, Terrence J. Monks
The Journal of pharmacology and experimental therapeutics April 2005 DOI: 10.1124/jpet.104.077628 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study (in vivo microdialysis in rats) Peer reviewed |
|---|---|
| Population | Rats administered MDMA by subcutaneous injection |
| Interventions | MDMA Acivicin |
| Topics | MDMA Serotonin |
| Key findings | Glutathione and N-acetylcysteine conjugates of N-methyl-alpha-MeDA are present in rat striatum after MDMA administration, and their concentrations increase with gamma-GT inhibition by acivicin, correlating with serotonin neurotoxicity. A synthesized conjugate is a potent serotonergic neurotoxicant, supporting the role of these metabolites in MDMA's neurotoxicity. |
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.