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
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- A review of acute effects of 3,4-methylenedioxymethamphetamine in healthy volunteers Journal of Psychopharmacology March 1, 2006
- The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine Biological Chemistry January 2, 2011
- MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant? Frontiers in Genetics 2012
- Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA Journal of Psychopharmacology May 20, 2006
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Cites 12
- Human Pharmacology of MDMA Therapeutic Drug Monitoring March 19, 2004
- Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Journal of Neuroscience July 1, 1998
- The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity Therapeutic Drug Monitoring March 19, 2004
- Glutathione and N-Acetylcysteine Conjugates of α-Methyldopamine Produce Serotonergic Neurotoxicity: Possible Role in Methylenedioxyamphetamine-Mediated Neurotoxicity Chemical Research in Toxicology November 19, 1999
- Role of hyperthermia in the protective action of clomethiazole against MDMA (‘ecstasy’)‐induced neurodegeneration, comparison with the novel NMDA channel blocker AR‐R15896AR British Journal of Pharmacology June 1, 1998
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