BACKGROUND: Data accumulated in the last decade indicate that N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of depression and the mechanism of action of antidepressants, although a direct inhibitory effect has been reported only in connection with tricyclic compounds, which interact with a wide range of receptors. METHODS: Using whole-cell patch-clamp recording in rat cortical cell cultures, we investigated whether the selective serotonin reuptake inhibitor fluoxetine, which has a much better adverse effect profile, has a direct effect on NMDA receptors, and we compared its action to that of the tricyclic desipramine. RESULTS: Both desipramine (concentration that causes 50% inhibition (IC(50)) = 3.13 microM) and fluoxetine (IC(50) = 10.51 microM) inhibited NMDA-evoked currents with similar efficacy in the clinically relevant low micromolar concentration range. However, in contrast to desipramine, the inhibition by fluoxetine was not voltage-dependent, and fluoxetine partially preserved its ability to associate with NMDA receptor in the presence of Mg(2+), suggesting different binding sites for the two drugs. CONCLUSIONS: The fact that different classes of antidepressants were found to be low-affinity NMDA antagonists suggests that direct inhibition of NMDA receptors may contribute to the clinical effects of antidepressants.
BACKGROUND: Data accumulated in the last decade indicate that N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of depression and the mechanism of action of antidepressants, although a direct inhibitory effect has been reported only in connection with tricyclic compounds, which interact with a wide range of receptors. METHODS: Using whole-cell patch-clamp recording in rat cortical cell cultures, we investigated whether the selective serotonin reuptake inhibitor fluoxetine, which has a much better adverse effect profile, has a direct effect on NMDA receptors, and we compared its action to that of the tricyclic desipramine. RESULTS: Both desipramine (concentration that causes 50% inhibition (IC(50)) = 3.13 microM) and fluoxetine (IC(50) = 10.51 microM) inhibited NMDA-evoked currents with similar efficacy in the clinically relevant low micromolar concentration range. However, in contrast to desipramine, the inhibition by fluoxetine was not voltage-dependent, and fluoxetine partially preserved its ability to associate with NMDA receptor in the presence of Mg(2+), suggesting different binding sites for the two drugs. CONCLUSIONS: The fact that different classes of antidepressants were found to be low-affinity NMDA antagonists suggests that direct inhibition of NMDA receptors may contribute to the clinical effects of antidepressants.
Authors: Andrea G Ludolph; Patrick T Udvardi; Ulrike Schaz; Carolin Henes; Oliver Adolph; Henry U Weigt; Joerg M Fegert; Tobias M Boeckers; Karl J Föhr Journal: Br J Pharmacol Date: 2010-05 Impact factor: 8.739
Authors: Gislaine Z Réus; Helena M Abelaira; Roberto B Stringari; Gabriel R Fries; Flávio Kapczinski; João Quevedo Journal: Metab Brain Dis Date: 2012-02-11 Impact factor: 3.584
Authors: Andiara E Freitas; Morgana Moretti; Josiane Budni; Grasiela O Balen; Sinara C Fernandes; Patricia O Veronezi; Melina Heller; Gustavo A Micke; Moacir G Pizzolatti; Ana Lúcia S Rodrigues Journal: J Med Food Date: 2013-11 Impact factor: 2.786