THIOETHER METABOLITES OF MDA AND MDMA INHIBIT hSERT FUNCTION AND SIMULTANEOUSLY STIMULATE DOPAMINE UPTAKE INTO hSERT-EXPRESSING SK-N-MC CELLS
Jones DC, Lau SS, Monks TJ.
University of Texas at Austin.u
J Pharmacol Exp Ther. 2004 May 28
ABSTRACT3,4-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 appears dependent on their systemic metabolism. 5-(Glutathion-S-yl)-alpha-methyldopamine (5-(GSyl)-alpha-MeDA) and 2,5-bis(glutathion-S-yl)-alpha-methyldopamine (2,5-bis(GSyl)-alpha-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)-alpha-MeDA and 2,5-bis(GSyl)-alpha-MeDA are more potent than MDA and MDMA (Ki = 69, 50, 107, and 102 mM, respectively) at inhibiting serotonin (5-HT) transport into SK-N-MC cells transiently transfected with the human serotonin transporter (hSERT). 5-(GSyl)-alpha-MeDA and 2,5-bis(GSyl)-alpha-MeDA 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)-alpha-MeDA and 2,5-bis(GSyl)-alpha-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 (hDAT)-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.Club drugs
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