TY - JOUR
T1 - Ecstasy metabolites and monoamine neurotransmitters upshift the Na+/K+ ATPase activity in mouse brain synaptosomes
AU - Barbosa, Daniel José
AU - Capela, João Paulo
AU - Ferreira, Luísa Maria
AU - Branco, Paula Sério
AU - Fernandes, Eduarda
AU - de Lourdes Bastos, Maria
AU - Carvalho, Félix
N1 - info:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FSAU-FCF%2F102958%2F2008/PT#
info:eu-repo/grantAgreement/FCT/3599-PPCDT/RECI%2FBBB-BQB%2F0230%2F2012/PT#
info:eu-repo/grantAgreement/FCT/FARH/SFRH%2FBD%2F64939%2F2009/PT#
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
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 [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.
KW - Acetylcysteine
KW - Adenosine
KW - Adenosine Triphosphatases
KW - Animals
KW - Antioxidants
KW - Brain
KW - Dopamine
KW - Levodopa
KW - Methylphenazonium Methosulfate
KW - Mice
KW - Neurotransmitter Agents
KW - Protein Kinases
KW - Serotonin
KW - Superoxides
KW - Synaptosomes
KW - metabolism
KW - brain synaptosome
UR - http://www.scopus.com/inward/record.url?scp=85138034748&partnerID=8YFLogxK
U2 - 10.1007/s00204-022-03370-7
DO - 10.1007/s00204-022-03370-7
M3 - Article
C2 - 36104498
SN - 0340-5761
VL - 96
SP - 3279
EP - 3290
JO - Archives Of Toxicology
JF - Archives Of Toxicology
IS - 12
ER -