Thioether metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine inhibit human serotonin transporter (hSERT) function and simultaneously stimulate dopamine uptake into hSERT-expressing SK-N-MC cells

Douglas C. Jones, Serrine Lau, Terrence Monks

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Abstract

3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are widely abused amphetamine derivatives that target the serotonin system. The serotonergic neurotoxicity of MDA and MDMA seems dependent on their systemic metabolism. 5-(Glutathion-S-yl)-α-methyldopamine [5-(GSyl)-α-MeDA] and 2,5-bis(glutathion-S-yl)-α-methyldopamine [2,5-bis(GSyl)-α-MeDA], metabolites of MDA and MDMA, are also selective serotonergic neurotoxicants and produce behavioral and neurochemical changes similar to those seen with MDA and MDMA. We now show that 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA are more potent than MDA and MDMA (Ki = 69, 50, 107, and 102 μM, respectively) at inhibiting 5-hydroxytryptamine (serotonin) transport into SK-N-MC cells transiently transfected with the human serotonin transporter (hSERT). Moreover, 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA simultaneously stimulated dopamine (DA) transport into the hSERT-expressing cells, an effect attenuated by fluoxetine, indicating that stimulated DA transport was hSERT-dependent. Finally, 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA, and to a lesser extent MDA and MDMA, induced a concentration and time-dependent increase in reactive oxygen species (ROS) in both hSERT and human dopamine transporter-transfected cells. Fluoxetine attenuated the increase in ROS generation in hSERT-expressing cells. The results are consistent with the view that the serotonergic neurotoxicity of MDA and MDMA may be mediated by the metabolism-dependent stimulation of DA transport into hSERT-expressing cells and ROS generation by redox active catecholthioether metabolites and DA.

Original languageEnglish (US)
Pages (from-to)298-306
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume311
Issue number1
DOIs
StatePublished - Oct 2004

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3,4-Methylenedioxyamphetamine
N-Methyl-3,4-methylenedioxyamphetamine
Serotonin Plasma Membrane Transport Proteins
Sulfides
Dopamine
Reactive Oxygen Species
Serotonin
Fluoxetine
Dopamine Plasma Membrane Transport Proteins
Amphetamine
Oxidation-Reduction
5-(glutathion-S-yl)methyldopamine

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Thioether metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine inhibit human serotonin transporter (hSERT) function and simultaneously stimulate dopamine uptake into hSERT-expressing SK-N-MC cells",
abstract = "3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are widely abused amphetamine derivatives that target the serotonin system. The serotonergic neurotoxicity of MDA and MDMA seems dependent on their systemic metabolism. 5-(Glutathion-S-yl)-α-methyldopamine [5-(GSyl)-α-MeDA] and 2,5-bis(glutathion-S-yl)-α-methyldopamine [2,5-bis(GSyl)-α-MeDA], metabolites of MDA and MDMA, are also selective serotonergic neurotoxicants and produce behavioral and neurochemical changes similar to those seen with MDA and MDMA. We now show that 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA are more potent than MDA and MDMA (Ki = 69, 50, 107, and 102 μM, respectively) at inhibiting 5-hydroxytryptamine (serotonin) transport into SK-N-MC cells transiently transfected with the human serotonin transporter (hSERT). Moreover, 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA simultaneously stimulated dopamine (DA) transport into the hSERT-expressing cells, an effect attenuated by fluoxetine, indicating that stimulated DA transport was hSERT-dependent. Finally, 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA, and to a lesser extent MDA and MDMA, induced a concentration and time-dependent increase in reactive oxygen species (ROS) in both hSERT and human dopamine transporter-transfected cells. Fluoxetine attenuated the increase in ROS generation in hSERT-expressing cells. The results are consistent with the view that the serotonergic neurotoxicity of MDA and MDMA may be mediated by the metabolism-dependent stimulation of DA transport into hSERT-expressing cells and ROS generation by redox active catecholthioether metabolites and DA.",
author = "Jones, {Douglas C.} and Serrine Lau and Terrence Monks",
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T1 - Thioether metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine inhibit human serotonin transporter (hSERT) function and simultaneously stimulate dopamine uptake into hSERT-expressing SK-N-MC cells

AU - Jones, Douglas C.

AU - Lau, Serrine

AU - Monks, Terrence

PY - 2004/10

Y1 - 2004/10

N2 - 3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are widely abused amphetamine derivatives that target the serotonin system. The serotonergic neurotoxicity of MDA and MDMA seems dependent on their systemic metabolism. 5-(Glutathion-S-yl)-α-methyldopamine [5-(GSyl)-α-MeDA] and 2,5-bis(glutathion-S-yl)-α-methyldopamine [2,5-bis(GSyl)-α-MeDA], metabolites of MDA and MDMA, are also selective serotonergic neurotoxicants and produce behavioral and neurochemical changes similar to those seen with MDA and MDMA. We now show that 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA are more potent than MDA and MDMA (Ki = 69, 50, 107, and 102 μM, respectively) at inhibiting 5-hydroxytryptamine (serotonin) transport into SK-N-MC cells transiently transfected with the human serotonin transporter (hSERT). Moreover, 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA simultaneously stimulated dopamine (DA) transport into the hSERT-expressing cells, an effect attenuated by fluoxetine, indicating that stimulated DA transport was hSERT-dependent. Finally, 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA, and to a lesser extent MDA and MDMA, induced a concentration and time-dependent increase in reactive oxygen species (ROS) in both hSERT and human dopamine transporter-transfected cells. Fluoxetine attenuated the increase in ROS generation in hSERT-expressing cells. The results are consistent with the view that the serotonergic neurotoxicity of MDA and MDMA may be mediated by the metabolism-dependent stimulation of DA transport into hSERT-expressing cells and ROS generation by redox active catecholthioether metabolites and DA.

AB - 3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are widely abused amphetamine derivatives that target the serotonin system. The serotonergic neurotoxicity of MDA and MDMA seems dependent on their systemic metabolism. 5-(Glutathion-S-yl)-α-methyldopamine [5-(GSyl)-α-MeDA] and 2,5-bis(glutathion-S-yl)-α-methyldopamine [2,5-bis(GSyl)-α-MeDA], metabolites of MDA and MDMA, are also selective serotonergic neurotoxicants and produce behavioral and neurochemical changes similar to those seen with MDA and MDMA. We now show that 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA are more potent than MDA and MDMA (Ki = 69, 50, 107, and 102 μM, respectively) at inhibiting 5-hydroxytryptamine (serotonin) transport into SK-N-MC cells transiently transfected with the human serotonin transporter (hSERT). Moreover, 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA simultaneously stimulated dopamine (DA) transport into the hSERT-expressing cells, an effect attenuated by fluoxetine, indicating that stimulated DA transport was hSERT-dependent. Finally, 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA, and to a lesser extent MDA and MDMA, induced a concentration and time-dependent increase in reactive oxygen species (ROS) in both hSERT and human dopamine transporter-transfected cells. Fluoxetine attenuated the increase in ROS generation in hSERT-expressing cells. The results are consistent with the view that the serotonergic neurotoxicity of MDA and MDMA may be mediated by the metabolism-dependent stimulation of DA transport into hSERT-expressing cells and ROS generation by redox active catecholthioether metabolites and DA.

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