PMID- 36104498 OWN - NLM STAT- MEDLINE DCOM- 20221024 LR - 20221222 IS - 1432-0738 (Electronic) IS - 0340-5761 (Linking) VI - 96 IP - 12 DP - 2022 Dec TI - Ecstasy metabolites and monoamine neurotransmitters upshift the Na(+)/K(+) ATPase activity in mouse brain synaptosomes. PG - 3279-3290 LID - 10.1007/s00204-022-03370-7 [doi] AB - 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 microM). 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 microM). 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. CI - (c) 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. FAU - Barbosa, Daniel Jose AU - Barbosa DJ AUID- ORCID: 0000-0002-1726-6011 AD - TOXRUN - Toxicology Research Unit, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal. daniel.barbosa@ibmc.up.pt. AD - Instituto de Investigacao e Inovacao em Saude (i3S), Universidade do Porto, Porto, Portugal. daniel.barbosa@ibmc.up.pt. AD - UCIBIO - Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. daniel.barbosa@ibmc.up.pt. FAU - Capela, Joao Paulo AU - Capela JP AUID- ORCID: 0000-0003-2607-1264 AD - UCIBIO - Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. AD - Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal. AD - FP-I3ID, Faculdade de Ciencias da Saude, Universidade Fernando Pessoa, Porto, Portugal. FAU - Ferreira, Luisa Maria AU - Ferreira LM AUID- ORCID: 0000-0001-8474-3925 AD - LAQV - REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, Caparica, Portugal. FAU - Branco, Paula Serio AU - Branco PS AUID- ORCID: 0000-0002-7312-8596 AD - LAQV - REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, Caparica, Portugal. FAU - Fernandes, Eduarda AU - Fernandes E AUID- ORCID: 0000-0001-6424-0976 AD - LAQV - REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. FAU - de Lourdes Bastos, Maria AU - de Lourdes Bastos M AUID- ORCID: 0000-0001-9895-503X AD - UCIBIO - Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. AD - Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal. FAU - Carvalho, Felix AU - Carvalho F AUID- ORCID: 0000-0003-3858-3494 AD - UCIBIO - Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. felixdc@ff.up.pt. AD - Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal. felixdc@ff.up.pt. LA - eng GR - SFRH/BD/64939/2009/Fundacao para a Ciencia e a Tecnologia/ GR - Project PTDC/SAU-FCF/102958/2008/Fundacao para a Ciencia e a Tecnologia/ PT - Journal Article DEP - 20220914 PL - Germany TA - Arch Toxicol JT - Archives of toxicology JID - 0417615 RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) RN - 333DO1RDJY (Serotonin) RN - 102-32-9 (3,4-Dihydroxyphenylacetic Acid) RN - VTD58H1Z2X (Dopamine) RN - WYQ7N0BPYC (Acetylcysteine) RN - 555-64-6 (alpha-methyldopamine) RN - 0 (Antioxidants) RN - 46627O600J (Levodopa) RN - EC 3.6.1.- (Adenosine Triphosphatases) RN - 11062-77-4 (Superoxides) RN - 299-11-6 (Methylphenazonium Methosulfate) RN - 0 (Neurotransmitter Agents) RN - K72T3FS567 (Adenosine) RN - EC 2.7.- (Protein Kinases) SB - IM MH - Animals MH - Mice MH - *N-Methyl-3,4-methylenedioxyamphetamine/toxicity MH - Synaptosomes/metabolism MH - Serotonin/metabolism MH - 3,4-Dihydroxyphenylacetic Acid/metabolism/pharmacology MH - Dopamine/metabolism MH - Acetylcysteine/pharmacology MH - Antioxidants/pharmacology MH - Levodopa/metabolism/pharmacology MH - Adenosine Triphosphatases/metabolism/pharmacology MH - Superoxides/metabolism MH - Methylphenazonium Methosulfate/metabolism/pharmacology MH - Brain MH - Neurotransmitter Agents/metabolism/pharmacology MH - Adenosine/metabolism MH - Protein Kinases/metabolism OTO - NOTNLM OT - 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") OT - MDMA brain effects OT - MDMA metabolites OT - Monoamine neurotransmitters OT - Na+/K+ ATPase OT - Synaptosomes EDAT- 2022/09/15 06:00 MHDA- 2022/10/25 06:00 CRDT- 2022/09/14 23:30 PHST- 2022/06/28 00:00 [received] PHST- 2022/08/25 00:00 [accepted] PHST- 2022/09/15 06:00 [pubmed] PHST- 2022/10/25 06:00 [medline] PHST- 2022/09/14 23:30 [entrez] AID - 10.1007/s00204-022-03370-7 [pii] AID - 10.1007/s00204-022-03370-7 [doi] PST - ppublish SO - Arch Toxicol. 2022 Dec;96(12):3279-3290. doi: 10.1007/s00204-022-03370-7. Epub 2022 Sep 14.