2,5-bis-(glutathion-S-yl)-α-methyldopamine, a putative metabolite of (±)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations

R. Timothy Miller, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

3,4-(±)-Methylenedioxyamphetamine (MDA) and 3,4-(±)-methylenedioxymethamphetamine (MDMA) are serotonergic neurotoxicants. However, when injected directly into brain, MDA and MDMA are not neurotoxic, suggesting that systemic metabolism plays an important role in the development of neurotoxicity. The nature of the metabolite(s) responsible for MDA- and MDMA-mediated neurotoxicity is unclear. α-Methyldopamine is a major metabolite of MDA and is readily oxidized to the o-quinone, followed by conjugation with glutathione (GSH). Because the conjugation of quinones with GSH frequently results in preservation or enhancement of biological (re)activity, we have been investigating the role of quinone-thioethers in the acute and long-term neurochemical changes observed after administration of MDA. Although intracerebroventricular (i.c.v.) administration of 5-(glutathion-S-yl)-α-methyldopamine (4 x 720 nmol) and 5-(N-acetylcystein-S-yl)-α-methyldopamine (1 x 7 nmol) to Sprague-Dawley rats produced overt behavioral changes similar to those seen following administration of MDA (93 μmol/kg, s.c.) they did not produce long-term decreases in brain serotonin (5-hydroxytryptamine, 5-HT) concentrations. In contrast, 2,5-bis-(glutathion-S-yl)α-methyldopamine (4 x 475 nmol) decreased 5-HT levers by 24%, 65% and 30% in the striatum, hippocampus and cortex, respectively, 7 days after injection. The relative sensitivity of the striatum, hippocampus and cortex to 2,5-bis-(glutathion-S-yl)-α-methyldopamine was the same as that observed for MDA; the absolute effects were greater with MDA. The effects of 2,5-bis-(glutathion-S-yl)α-methyldopamine were also selective for serotonergic nerve terminal fields, in that 5-HT levels were unaffected in regions of the cell bodies. Because 2,5-bis-(glutathion-S-yl)α-methyldopamine caused long-term depletion in 5-HT without adversely affecting the dopaminergic system, it also mimics the selectivity of MDA/MDMA. The data imply a possible role for quinone-thioethers in the neurobehavioral and neurotoxicological effects of MDA/MDMA.

Original languageEnglish (US)
Pages (from-to)173-180
Number of pages8
JournalEuropean Journal of Pharmacology
Volume323
Issue number2-3
DOIs
StatePublished - Apr 4 1997
Externally publishedYes

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3,4-Methylenedioxyamphetamine
Serotonin
N-Methyl-3,4-methylenedioxyamphetamine
Brain
Deoxyepinephrine
Sulfides
Hippocampus
5-(glutathion-S-yl)methyldopamine
Quinones
Glutathione
Sprague Dawley Rats

Keywords

  • α-methyldopamine
  • 5-HT (5-hydroxytryptamine, serotonin)
  • Glutathione
  • MDA (3,4-Methylenedioxyamphetamine)
  • MDMA (3,4-Methylenedioxymethamphetamine)
  • Neurotoxicity

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

@article{2430c8362fdf4a2f9c426aeaf896b9fb,
title = "2,5-bis-(glutathion-S-yl)-α-methyldopamine, a putative metabolite of (±)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations",
abstract = "3,4-(±)-Methylenedioxyamphetamine (MDA) and 3,4-(±)-methylenedioxymethamphetamine (MDMA) are serotonergic neurotoxicants. However, when injected directly into brain, MDA and MDMA are not neurotoxic, suggesting that systemic metabolism plays an important role in the development of neurotoxicity. The nature of the metabolite(s) responsible for MDA- and MDMA-mediated neurotoxicity is unclear. α-Methyldopamine is a major metabolite of MDA and is readily oxidized to the o-quinone, followed by conjugation with glutathione (GSH). Because the conjugation of quinones with GSH frequently results in preservation or enhancement of biological (re)activity, we have been investigating the role of quinone-thioethers in the acute and long-term neurochemical changes observed after administration of MDA. Although intracerebroventricular (i.c.v.) administration of 5-(glutathion-S-yl)-α-methyldopamine (4 x 720 nmol) and 5-(N-acetylcystein-S-yl)-α-methyldopamine (1 x 7 nmol) to Sprague-Dawley rats produced overt behavioral changes similar to those seen following administration of MDA (93 μmol/kg, s.c.) they did not produce long-term decreases in brain serotonin (5-hydroxytryptamine, 5-HT) concentrations. In contrast, 2,5-bis-(glutathion-S-yl)α-methyldopamine (4 x 475 nmol) decreased 5-HT levers by 24{\%}, 65{\%} and 30{\%} in the striatum, hippocampus and cortex, respectively, 7 days after injection. The relative sensitivity of the striatum, hippocampus and cortex to 2,5-bis-(glutathion-S-yl)-α-methyldopamine was the same as that observed for MDA; the absolute effects were greater with MDA. The effects of 2,5-bis-(glutathion-S-yl)α-methyldopamine were also selective for serotonergic nerve terminal fields, in that 5-HT levels were unaffected in regions of the cell bodies. Because 2,5-bis-(glutathion-S-yl)α-methyldopamine caused long-term depletion in 5-HT without adversely affecting the dopaminergic system, it also mimics the selectivity of MDA/MDMA. The data imply a possible role for quinone-thioethers in the neurobehavioral and neurotoxicological effects of MDA/MDMA.",
keywords = "α-methyldopamine, 5-HT (5-hydroxytryptamine, serotonin), Glutathione, MDA (3,4-Methylenedioxyamphetamine), MDMA (3,4-Methylenedioxymethamphetamine), Neurotoxicity",
author = "Miller, {R. Timothy} and Serrine Lau and Terrence Monks",
year = "1997",
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doi = "10.1016/S0014-2999(97)00044-7",
language = "English (US)",
volume = "323",
pages = "173--180",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
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TY - JOUR

T1 - 2,5-bis-(glutathion-S-yl)-α-methyldopamine, a putative metabolite of (±)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations

AU - Miller, R. Timothy

AU - Lau, Serrine

AU - Monks, Terrence

PY - 1997/4/4

Y1 - 1997/4/4

N2 - 3,4-(±)-Methylenedioxyamphetamine (MDA) and 3,4-(±)-methylenedioxymethamphetamine (MDMA) are serotonergic neurotoxicants. However, when injected directly into brain, MDA and MDMA are not neurotoxic, suggesting that systemic metabolism plays an important role in the development of neurotoxicity. The nature of the metabolite(s) responsible for MDA- and MDMA-mediated neurotoxicity is unclear. α-Methyldopamine is a major metabolite of MDA and is readily oxidized to the o-quinone, followed by conjugation with glutathione (GSH). Because the conjugation of quinones with GSH frequently results in preservation or enhancement of biological (re)activity, we have been investigating the role of quinone-thioethers in the acute and long-term neurochemical changes observed after administration of MDA. Although intracerebroventricular (i.c.v.) administration of 5-(glutathion-S-yl)-α-methyldopamine (4 x 720 nmol) and 5-(N-acetylcystein-S-yl)-α-methyldopamine (1 x 7 nmol) to Sprague-Dawley rats produced overt behavioral changes similar to those seen following administration of MDA (93 μmol/kg, s.c.) they did not produce long-term decreases in brain serotonin (5-hydroxytryptamine, 5-HT) concentrations. In contrast, 2,5-bis-(glutathion-S-yl)α-methyldopamine (4 x 475 nmol) decreased 5-HT levers by 24%, 65% and 30% in the striatum, hippocampus and cortex, respectively, 7 days after injection. The relative sensitivity of the striatum, hippocampus and cortex to 2,5-bis-(glutathion-S-yl)-α-methyldopamine was the same as that observed for MDA; the absolute effects were greater with MDA. The effects of 2,5-bis-(glutathion-S-yl)α-methyldopamine were also selective for serotonergic nerve terminal fields, in that 5-HT levels were unaffected in regions of the cell bodies. Because 2,5-bis-(glutathion-S-yl)α-methyldopamine caused long-term depletion in 5-HT without adversely affecting the dopaminergic system, it also mimics the selectivity of MDA/MDMA. The data imply a possible role for quinone-thioethers in the neurobehavioral and neurotoxicological effects of MDA/MDMA.

AB - 3,4-(±)-Methylenedioxyamphetamine (MDA) and 3,4-(±)-methylenedioxymethamphetamine (MDMA) are serotonergic neurotoxicants. However, when injected directly into brain, MDA and MDMA are not neurotoxic, suggesting that systemic metabolism plays an important role in the development of neurotoxicity. The nature of the metabolite(s) responsible for MDA- and MDMA-mediated neurotoxicity is unclear. α-Methyldopamine is a major metabolite of MDA and is readily oxidized to the o-quinone, followed by conjugation with glutathione (GSH). Because the conjugation of quinones with GSH frequently results in preservation or enhancement of biological (re)activity, we have been investigating the role of quinone-thioethers in the acute and long-term neurochemical changes observed after administration of MDA. Although intracerebroventricular (i.c.v.) administration of 5-(glutathion-S-yl)-α-methyldopamine (4 x 720 nmol) and 5-(N-acetylcystein-S-yl)-α-methyldopamine (1 x 7 nmol) to Sprague-Dawley rats produced overt behavioral changes similar to those seen following administration of MDA (93 μmol/kg, s.c.) they did not produce long-term decreases in brain serotonin (5-hydroxytryptamine, 5-HT) concentrations. In contrast, 2,5-bis-(glutathion-S-yl)α-methyldopamine (4 x 475 nmol) decreased 5-HT levers by 24%, 65% and 30% in the striatum, hippocampus and cortex, respectively, 7 days after injection. The relative sensitivity of the striatum, hippocampus and cortex to 2,5-bis-(glutathion-S-yl)-α-methyldopamine was the same as that observed for MDA; the absolute effects were greater with MDA. The effects of 2,5-bis-(glutathion-S-yl)α-methyldopamine were also selective for serotonergic nerve terminal fields, in that 5-HT levels were unaffected in regions of the cell bodies. Because 2,5-bis-(glutathion-S-yl)α-methyldopamine caused long-term depletion in 5-HT without adversely affecting the dopaminergic system, it also mimics the selectivity of MDA/MDMA. The data imply a possible role for quinone-thioethers in the neurobehavioral and neurotoxicological effects of MDA/MDMA.

KW - α-methyldopamine

KW - 5-HT (5-hydroxytryptamine, serotonin)

KW - Glutathione

KW - MDA (3,4-Methylenedioxyamphetamine)

KW - MDMA (3,4-Methylenedioxymethamphetamine)

KW - Neurotoxicity

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U2 - 10.1016/S0014-2999(97)00044-7

DO - 10.1016/S0014-2999(97)00044-7

M3 - Article

C2 - 9128836

AN - SCOPUS:0030951385

VL - 323

SP - 173

EP - 180

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 2-3

ER -