Serotonergic neurotoxicity of 3,4-(±)-methylenedioxyamphetamine and 3,4-(±)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of γ-glutamyl transpeptidase

F. Bai, D. C. Jones, Serrine Lau, Terrence Monks

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Abstract

Reactive metabolites play an important role in 3,4-(±)-methylenedioxyamphetamine (MDA) and 3,4-(±)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of such metabolites remains unclear. 5-(Glutathion-S-yl)-α-methyldopamine (5-GSyl-α-MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-α-MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of γ-glutamyl transpeptidase (γ-GT) suggesting competition between intact 5-GSyl-α-MeDA and GSH for the putative GSH transporter. γ-GT is enriched in blood - brain barrier endothelial cells and is the only enzyme known to cleave the γ-glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial γ-GT activity by 60%, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid (5-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell γ-GT at the blood - brain barrier likely enhances the uptake into brain of thioether metabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-α-MeDA and 2,5-bis-(glutathion-S-yl)-α-MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.

Original languageEnglish (US)
Pages (from-to)863-870
Number of pages8
JournalChemical Research in Toxicology
Volume14
Issue number7
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

3,4-Methylenedioxyamphetamine
N-Methyl-3,4-methylenedioxyamphetamine
acivicin
gamma-Glutamyltransferase
Metabolites
Brain
Sulfides
Glutathione
Rats
Serotonin
Endothelial cells
Blood-Brain Barrier
Animals
Endothelial Cells
Glial Fibrillary Acidic Protein
Presynaptic Terminals
Microvessels
Bile
Hypothalamus
Hippocampus

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

@article{4ecc1ae190dd494da709f09f9ac3dcd4,
title = "Serotonergic neurotoxicity of 3,4-(±)-methylenedioxyamphetamine and 3,4-(±)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of γ-glutamyl transpeptidase",
abstract = "Reactive metabolites play an important role in 3,4-(±)-methylenedioxyamphetamine (MDA) and 3,4-(±)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of such metabolites remains unclear. 5-(Glutathion-S-yl)-α-methyldopamine (5-GSyl-α-MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-α-MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of γ-glutamyl transpeptidase (γ-GT) suggesting competition between intact 5-GSyl-α-MeDA and GSH for the putative GSH transporter. γ-GT is enriched in blood - brain barrier endothelial cells and is the only enzyme known to cleave the γ-glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial γ-GT activity by 60{\%}, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid (5-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell γ-GT at the blood - brain barrier likely enhances the uptake into brain of thioether metabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-α-MeDA and 2,5-bis-(glutathion-S-yl)-α-MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.",
author = "F. Bai and Jones, {D. C.} and Serrine Lau and Terrence Monks",
year = "2001",
doi = "10.1021/tx010011l",
language = "English (US)",
volume = "14",
pages = "863--870",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
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TY - JOUR

T1 - Serotonergic neurotoxicity of 3,4-(±)-methylenedioxyamphetamine and 3,4-(±)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of γ-glutamyl transpeptidase

AU - Bai, F.

AU - Jones, D. C.

AU - Lau, Serrine

AU - Monks, Terrence

PY - 2001

Y1 - 2001

N2 - Reactive metabolites play an important role in 3,4-(±)-methylenedioxyamphetamine (MDA) and 3,4-(±)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of such metabolites remains unclear. 5-(Glutathion-S-yl)-α-methyldopamine (5-GSyl-α-MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-α-MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of γ-glutamyl transpeptidase (γ-GT) suggesting competition between intact 5-GSyl-α-MeDA and GSH for the putative GSH transporter. γ-GT is enriched in blood - brain barrier endothelial cells and is the only enzyme known to cleave the γ-glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial γ-GT activity by 60%, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid (5-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell γ-GT at the blood - brain barrier likely enhances the uptake into brain of thioether metabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-α-MeDA and 2,5-bis-(glutathion-S-yl)-α-MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.

AB - Reactive metabolites play an important role in 3,4-(±)-methylenedioxyamphetamine (MDA) and 3,4-(±)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of such metabolites remains unclear. 5-(Glutathion-S-yl)-α-methyldopamine (5-GSyl-α-MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-α-MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of γ-glutamyl transpeptidase (γ-GT) suggesting competition between intact 5-GSyl-α-MeDA and GSH for the putative GSH transporter. γ-GT is enriched in blood - brain barrier endothelial cells and is the only enzyme known to cleave the γ-glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial γ-GT activity by 60%, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid (5-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell γ-GT at the blood - brain barrier likely enhances the uptake into brain of thioether metabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-α-MeDA and 2,5-bis-(glutathion-S-yl)-α-MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.

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U2 - 10.1021/tx010011l

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