title: Pro-oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes.
abstract: OBJECTIVE
  3,4-Methylenedioxymethamphetamine (MDMA or 'Ecstasy') is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of MDMA are not clear at present, but the metabolism of dopamine and 5-HT by monoamine oxidase (MAO), as well as the hepatic biotransformation of MDMA into pro-oxidant reactive metabolites is thought to contribute to its adverse effects.
  
  
  METHODS
  Using mouse brain synaptosomes, we evaluated the pro-oxidant effects of MDMA and its metabolites, α-methyldopamine (α-MeDA), N-methyl-α-methyldopamine (N-Me-α-MeDA) and 5-(glutathion-S-yl)-α-methyldopamine [5-(GSH)-α-MeDA], as well as those of 5-HT, dopamine, l-DOPA and 3,4-dihydroxyphenylacetic acid (DOPAC).
  
  
  RESULTS
  5-HT, dopamine, l-DOPA, DOPAC and MDMA metabolites α-MeDA, N-Me-α-MeDA and 5-(GSH)-α-MeDA, concentration- and time-dependently increased H(2) O(2 ) production, which was significantly reduced by the antioxidants N-acetyl-l-cysteine (NAC), ascorbic acid and melatonin. From experiments with MAO inhibitors, it was observed that H(2) O(2)  generation induced by 5-HT was totally dependent on MAO-related metabolism, while for dopamine, it was a minor pathway. The MDMA metabolites, dopamine, l-DOPA and DOPAC concentration-dependently increased quinoproteins formation and, like 5-HT, altered the synaptosomal glutathione status. Finally, none of the compounds modified the number of polarized mitochondria in the synaptosomal preparations, and the compounds' pro-oxidant effects were unaffected by prior mitochondrial depolarization, excluding a significant role for mitochondrial-dependent mechanisms of toxicity in this experimental model.
  
  
  CONCLUSIONS
  MDMA metabolites along with high levels of monoamine neurotransmitters can be major effectors of neurotoxicity induced by Ecstasy.
authors.affiliation: REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal. daniel.barbosa@ff.up.pt
authors.forename: Daniel José
authors.initials: DJ
authors.lastname: Barbosa
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Capela
authors.forename: Jorge Ma
authors.initials: JM
authors.lastname: Oliveira
authors.forename: Renata
authors.initials: R
authors.lastname: Silva
authors.forename: Luísa Maria
authors.initials: LM
authors.lastname: Ferreira
authors.forename: Filipa
authors.initials: F
authors.lastname: Siopa
authors.forename: Paula Sério
authors.initials: PS
authors.lastname: Branco
authors.forename: Eduarda
authors.initials: E
authors.lastname: Fernandes
authors.forename: José Alberto
authors.initials: JA
authors.lastname: Duarte
authors.forename: Maria
authors.initials: M
authors.lastname: de Lourdes Bastos
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D015104:3,4-Methylenedioxyamphetamine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D003846:Deoxyepinephrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006213:Hallucinogens / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects* / Q000502:physiology
chemical_list: C096088:5-(glutathion-S-yl)methyldopamine; D000975:Antioxidants; D006213:Hallucinogens; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D007980:Levodopa; D015104:3,4-Methylenedioxyamphetamine; C023492:alpha-methyldopamine; D006861:Hydrogen Peroxide; D005978:Glutathione; D003846:Deoxyepinephrine; D004298:Dopamine