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TOXICOLOGY

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

Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas

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)--methyldopamine [5-(GSyl)--MeDA] and 2,5-bis(glutathion-S-yl)--methyldopamine [2,5-bis(GSyl)--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)--MeDA and 2,5-bis(GSyl)--MeDA are more potent than MDA and MDMA (K_i = 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)--MeDA and 2,5-bis(GSyl)--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)--MeDA and 2,5-bis(GSyl)--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.

Address correspondence to: Dr. Terrence J. Monks, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, 1703 E. Mabel St., Tucson, AZ 85721-0207. E-mail: scouser{at}pharmacy.arizona.edu

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