Ecstasy metabolites and monoamine neurotransmitters upshift the Na +/K + ATPase activity in mouse brain synaptosomes

Daniel José Barbosa, João Paulo Capela, Luísa Maria Ferreira, Eduarda Fernandes, Maria de Lourdes Bastos, Félix Carvalho, Paula Cristina de Sério Branco

Research output: Contribution to journalArticlepeer-review

Abstract

3,4-Methylenedioximethamphetamine (MDMA; "ecstasy") is a psychotropic drug with well-known neurotoxic effects mediated by hitherto not fully understood mechanisms. The Na +- and K +-activated adenosine 5'-triphosphatase (Na +/K + ATPase), by maintaining the ion gradient across the cell membrane, regulates neuronal excitability. Thus, a perturbation of its function strongly impacts cell homeostasis, ultimately leading to neuronal dysfunction and death. Nevertheless, whether MDMA affects the Na +/K + ATPase remains unknown. In this study, we used synaptosomes obtained from whole mouse brain to test the effects of MDMA, three of its major metabolites [α-methyldopamine, N-methyl-α-methyldopamine and 5-(glutathion-S-yl)-α-methyldopamine], serotonin (5-HT), dopamine, 3,4-dihydroxy-L-phenylalanine (L-Dopa) and 3,4-dihydroxyphenylacetic acid (DOPAC) on the Na +/K + ATPase function. A concentration-dependent increase of Na +/K + ATPase activity was observed in synaptosomes exposed to the tested compounds (concentrations ranging from 0.0625 to 200 µM). These effects were independent of protein kinases A and C activities. Nevertheless, a rescue of the compounds' effects was observed in synaptosomes pre-incubated with the antioxidant N-acetylcysteine (1 mM), suggesting a role for reactive species-regulated pathways on the Na +/K + ATPase effects. In agreement with this hypothesis, a similar increase in the pump activity was found in synaptosomes exposed to the chemical generator of superoxide radicals, phenazine methosulfate (1-250 µM). This study demonstrates the ability of MDMA metabolites, monoamine neurotransmitters, L-Dopa and DOPAC to alter the Na +/K + ATPase function. This could represent a yet unknown mechanism of action of MDMA and its metabolites in the brain.

Original languageEnglish
Pages (from-to)3279–3290
Number of pages12
JournalArchives Of Toxicology
Volume96
Issue number12
DOIs
Publication statusE-pub ahead of print - 14 Sep 2022

Keywords

  • Acetylcysteine
  • Adenosine
  • Adenosine Triphosphatases
  • Animals
  • Antioxidants
  • Brain
  • Dopamine
  • Levodopa
  • Methylphenazonium Methosulfate
  • Mice
  • Neurotransmitter Agents
  • Protein Kinases
  • Serotonin
  • Superoxides
  • Synaptosomes
  • metabolism
  • brain synaptosome

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