Szasz Bernadett K, Mike Arpad, Karoly Robert, Gerevich Zoltan, Illes Peter, Vizi E Sylvester, Kiss Janos P
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u.43, Budapest, Hungary.
Biol Psychiatry. 2007 Dec 1;62(11):1303-9. doi: 10.1016/j.biopsych.2007.04.014. Epub 2007 Jul 20.
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.
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.
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.
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.
过去十年积累的数据表明，N-甲基-D-天冬氨酸（NMDA）受体可能参与抑郁症的病理生理学过程以及抗抑郁药的作用机制，尽管仅报道了三环类化合物与NMDA受体存在直接抑制作用，而三环类化合物可与多种受体相互作用。
我们采用大鼠皮质细胞培养的全细胞膜片钳记录技术，研究具有更好不良反应谱的选择性5-羟色胺再摄取抑制剂氟西汀是否对NMDA受体有直接作用，并将其作用与三环类药物地昔帕明进行比较。
在临床相关的低微摩尔浓度范围内，地昔帕明（半数抑制浓度（IC50）=3.13微摩尔）和氟西汀（IC50=10.51微摩尔）均以相似的效力抑制NMDA诱发的电流。然而，与地昔帕明不同，氟西汀的抑制作用不依赖电压，且在存在镁离子（Mg2+）的情况下，氟西汀仍部分保留其与NMDA受体结合的能力，这表明两种药物的结合位点不同。
不同类别的抗抑郁药被发现是低亲和力的NMDA拮抗剂，这一事实表明对NMDA受体的直接抑制作用可能有助于抗抑郁药的临床疗效。
