Ecstasy metabolites and monoamine neurotransmitters upshift the Na+/K+ ATPase activity in mouse brain synaptosomes.
Daniel José Barbosa, João Paulo Capela, Luísa Maria Ferreira, Paula Sério Branco, Eduarda Fernandes, Maria de Lourdes Bastos, Félix Carvalho
Archives of Toxicology December 2022 DOI: 10.1007/s00204-022-03370-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro laboratory study Peer reviewed |
|---|---|
| Population | Synaptosomes prepared from whole mouse brain |
| Interventions | MDMA α-methyldopamine N-methyl-α-methyldopamine 5-(glutathion-S-yl)-α-methyldopamine serotonin (5-HT) dopamine L-Dopa DOPAC N-acetylcysteine phenazine methosulfate |
| Dose | 0.0625 to 200 µM for tested compounds; N-acetylcysteine 1 mM; phenazine methosulfate 1-250 µM |
| Topics | MDMA |
| Keywords | 3,4-Methylenedioxymethamphetamine MDMA MDMA Brain Effects MDMA Metabolites Monoamine neurotransmitters Na+/k+ atpase Synaptosomes |
| Key points | MDMA, three of its major metabolites, serotonin, dopamine, L-Dopa, and DOPAC each increased Na+/K+ ATPase activity in mouse brain synaptosomes in a concentration-dependent manner (0.0625-200 µM). The increases were independent of protein kinases A and C but were prevented by the antioxidant N-acetylcysteine (1 mM), and the superoxide generator phenazine methosulfate (1-250 µM) similarly increased pump activity, suggesting reactive species-regulated pathways. The authors propose this as a previously unknown mechanism of MDMA and metabolite action in the brain. |
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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and 9 more in the library