Direct Inhibitory Effect of Fluoxetine on N-Methyl-D-Aspartate Receptors in the Central Nervous System

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 (IC50) = 3.13 μM) and fluoxetine (IC50 = 10.51 μM) 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 Mg2+, 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.