Abstract
3,4-Methylenedioxyamphetamine (MDA) and 3,4-methyl-enedioxymethamphetamine (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-hy-droxytryptamine (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 catechol-thioether metabolites and DA.
Footnotes
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Portions of this work were supported by an award (DA10832) from the National Institute of Drug Abuse to T.J.M.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.069260.
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ABBREVIATIONS: MDA, 3,4-methylenedioxyamphetamine; MDMA, 3,4-methylenedioxymethamphetamine (ecstasy); 5-HT, 5-hydroxytryptamine (serotonin); SERT, serotonin transporter; GSH, glutathione; 5-(GSyl)-α-MeDA, 5-(glutathion-S-yl)-α-methyldopamine; 2,5-bis(GSyl)-α-MeDA, 2,5-bis(glutathion-S-yl)-α-methyldopamine; DA, dopamine; MAO, monoamine oxidase; ROS, reactive oxygen species; HPLC, high-performance liquid chromatography; hSERT, human serotonin transporter; hDAT, human dopamine transporter; DAT, dopamine transporter; KR, Krebs-Ringer; DCF-DA, dichlorofluorescein diacetate; DCF, dichlorofluorescein.
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↵1 Current address: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, 1703 E. Mabel St., Tucson, AZ 85721-0207.
- Received March 31, 2004.
- Accepted May 27, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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