期刊
BIOLOGICAL PSYCHIATRY
卷 62, 期 11, 页码 1303-1309出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2007.04.014
关键词
antidepressant action; depression; desipramine; fluoxetine; NMDA receptor; whole cell patch clamp
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 mu M) and fluoxetine (IC50 = 10.51 mu M) 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.
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