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

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Barbosa, DJ (Author) Other; Capela, JP (Author) Other; Ferreira, LM (Author) Other; Branco, PS (Author) Other; Eduarda Fernandes (Author) FFUP; Maria de Lourdes Bastos (Author) FFUP; Felix Carvalho (Author) FFUP

Journal

Title: Archives of Toxicology

Vol. 96

Pages: 3279-3290

ISSN: 0340-5761

Publisher: Springer Nature

Indexing

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Other information

Authenticus ID: P-00X-7FD

DOI: 10.1007/s00204-022-03370-7

Abstract (EN): 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 [alpha-methyldopamine, N-methyl-alpha-methyldopamine and 5-(glutathion-S-yl)-alpha-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 mu M). 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 mu M). 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12