Serotonergic neurotoxic metabolites of ecstasy identified in rat brain
- PMID: 15634943
- DOI: 10.1124/jpet.104.077628
Serotonergic neurotoxic metabolites of ecstasy identified in rat brain
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.
Similar articles
-
Serotonergic neurotoxicity of 3,4-(+/-)-methylenedioxyamphetamine and 3,4-(+/-)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of gamma-glutamyl transpeptidase.Chem Res Toxicol. 2001 Jul;14(7):863-70. doi: 10.1021/tx010011l. Chem Res Toxicol. 2001. PMID: 11453733
-
Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity.Chem Res Toxicol. 1999 Dec;12(12):1150-7. doi: 10.1021/tx990084t. Chem Res Toxicol. 1999. PMID: 10604863
-
Accumulation of neurotoxic thioether metabolites of 3,4-(+/-)-methylenedioxymethamphetamine in rat brain.J Pharmacol Exp Ther. 2008 Jan;324(1):284-91. doi: 10.1124/jpet.107.128785. Epub 2007 Sep 28. J Pharmacol Exp Ther. 2008. PMID: 17906065
-
The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity.Ther Drug Monit. 2004 Apr;26(2):132-6. doi: 10.1097/00007691-200404000-00008. Ther Drug Monit. 2004. PMID: 15228153 Review.
-
[Biomimetic electrochemical synthesis of quinol-thioether conjugates: their implication in the serotonergic neurotoxicity of amphetamine derivatives].Ann Pharm Fr. 2003 May;61(3):164-72. Ann Pharm Fr. 2003. PMID: 12714929 Review. French.
Cited by
-
Ecstasy metabolites and monoamine neurotransmitters upshift the Na+/K+ ATPase activity in mouse brain synaptosomes.Arch Toxicol. 2022 Dec;96(12):3279-3290. doi: 10.1007/s00204-022-03370-7. Epub 2022 Sep 14. Arch Toxicol. 2022. PMID: 36104498
-
Concurrent Inhibition of Vesicular Monoamine Transporter 2 Does Not Protect Against 3,4-Methylenedioxymethamphetamine (Ecstasy) Induced Neurotoxicity.Toxicol Sci. 2019 Jul 1;170(1):157-166. doi: 10.1093/toxsci/kfz085. Toxicol Sci. 2019. PMID: 30923810 Free PMC article.
-
"Ecstasy" toxicity to adolescent rats following an acute low binge dose.BMC Pharmacol Toxicol. 2016 Jun 28;17(1):28. doi: 10.1186/s40360-016-0070-0. BMC Pharmacol Toxicol. 2016. PMID: 27349892 Free PMC article.
-
Multidrug resistance protein 1 (MRP1, ABCC1), a "multitasking" ATP-binding cassette (ABC) transporter.J Biol Chem. 2014 Nov 7;289(45):30880-8. doi: 10.1074/jbc.R114.609248. Epub 2014 Oct 3. J Biol Chem. 2014. PMID: 25281745 Free PMC article. Review.
-
Attenuation of ecstasy-induced neurotoxicity by N-acetylcysteine.Metab Brain Dis. 2015 Feb;30(1):171-81. doi: 10.1007/s11011-014-9598-0. Epub 2014 Aug 6. Metab Brain Dis. 2015. PMID: 25096201
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous