The role of alpha-methyldopamine thioethers in the serotonergic neurotoxicity of MDA and MDMA

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dc.contributor.advisorDuvauchelle, Christine L.en
dc.contributor.advisorMonks, Terrence J.en
dc.creatorJones, Douglas Campbellen
dc.date.accessioned2008-08-28T22:29:03Zen
dc.date.available2008-08-28T22:29:03Zen
dc.date.issued2004en
dc.descriptiontexten
dc.description.abstract3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are widely abused amphetamine derivatives that target the serotonin (5-HT) system. The direct administration of MDA/MDMA into the brain fails to reproduce the ìserotonin syndromeî that defines the neurotoxicity of MDA/MDMA; thus, the neurotoxicity of MDA and MDMA appears dependent on their systemic metabolism. 5-(Glutathion-S-yl)-α- methyldopamine and 2,5-bis(glutathion-S-yl)-α-methyldopamine, metabolites of MDA/MDMA, are potent serotonergic neurotoxicants, and produce behavioral and neurochemical changes similar to those observed with MDA/MDMA. Therefore, we investigated the transport of α- MeDA thioethers into the brain, and the biochemical mechanisms underling the development of neurotoxicity. Collection of extracellular fluid samples with microdialysis and subsequent analysis by HPLC and LC-MS/MS lead to the identification of thioether metabolites of N-Me-α- MeDA in the brain following peripheral administration of MDMA. GSH conjugate concentrations increased rapidly prior to a rapid decrease, whereas brain concentrations of the Nacetylcysteine conjugates increased slowly. Correlations exist between the concentration of NMe-α-MeDA in the brain and decreases in brain 5-HT and 5-HIAA induced by MDMA. MDMA is demethylenated to N-Me-α-MeDA; we therefore, examined the potential neurotoxicity of 5- (NAC)-N-Me-α-MeDA. Following intrastriatal injections, 5-(NAC)-N-Me-α-MeDA produced decreases in 5-HT, 5-HIAA, and dopamine (DA). We subsequently utilized three different cell models to investigate the potential mechanisms by which 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)- α-MeDA induce neurotoxicity. 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA are more potent than MDA/MDMA at inhibiting 5-HT transport into i) SK-N-MC cells transfected with the human serotonin transporter (SERT), ii) JAR cells, and iii) primary rat hippocampal cells. 5- (GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA induced an increase in (DA) transport into all three cell models, an effect attenuated by fluoxetine, indicating that DA transport was SERTdependent. 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA increased reactive oxygen species (ROS) in each cell model. Fluoxetine attenuated the increase in ROS generation in hSERTexpressing cells. Finally, 5-(GSyl)-α-MeDA and 2,5-bis(GSyl)-α-MeDA produced loss of cell viability and apoptosis in SERT-transfected SK-N-MC cells, JAR cells and hippocampal cells. These results are consistent with the view that the serotonergic neurotoxicity of MDA/MDMA requires i) the systemic metabolism to α-MeDA and N-Me-α-MeDA and conjugation to GSH, and ii) is likely mediated through ROS generation and the stimulation of DA transport into serotonergic neurons.
dc.description.departmentPharmacyen
dc.format.mediumelectronicen
dc.identifierb60805262en
dc.identifier.oclc68626459en
dc.identifier.proqst3143898en
dc.identifier.urihttp://hdl.handle.net/2152/2029en
dc.language.isoengen
dc.rightsCopyright is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works.en
dc.subject.lcshEcstasy (Drug)--Metabolismen
dc.subject.lcshSerotoninergic mechanismsen
dc.subject.lcshNeurotoxicologyen
dc.subject.lcshAlpha-methyldopamineen
dc.titleThe role of alpha-methyldopamine thioethers in the serotonergic neurotoxicity of MDA and MDMAen
dc.type.genreThesisen

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