Inhibition of N-methyl-D-aspartate receptor function appears to be one of the common actions for antidepressants

Abstract

In order to explore the possible common action mechanisms of three kinds of classical antidepressants, inhibition of drugs on the N-methyl-D-aspartate (NMDA)-Ca(2)-nitric oxide synthase (NOS) signal pathway was observed. With 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and lactic dehydrogenase (LDH) assay, classical antidepressants, desipramine (1, 10 microM), fluoxetine (0.625-10 microM) or moclobemide (2.5, 10 microM) antagonized NMDA 300 M induced-lesion in PC12 cells. Using fura-2/AM (acetoxymethyl ester) labelling assay, desipramine or fluoxetine at doses 1, 5 microM attenuated the intracellular Ca(2) overload induced by NMDA 200 microM for 24 h in PC12 cells. Meanwhile, using confocal microscope, it was also found that desipramine 5 microM, fluoxetine 2.5 microM or moclobemide 10 microM decreased the NMDA 20 microM induced intracellular Ca(2) overload in primarily cultured rat hippocampal neurons. Furthermore, desipramine (1, 5 microM), fluoxetine (1, 5 microM) or moclobemide (2.5, 10 microM) significantly inhibited NOS activity in NMDA (300 microM) treated PC12 cells for 4h. In summary, we suggest that inhibition on the function of NMDA-Ca(2) -NOS signal pathway appears to be one of the common actions for antidepressants despite their remarkably different structures, which is expected to have great implication for the evaluation and screening in vitro of new antidepressants.

Neuronal NOS Inhibitor and Conventional Antidepressant Drugs Attenuate Stress-induced Fos Expression in Overlapping Brain Regions

“…This suggests that, besides increasing monoamine levels in the brain by directly inhibiting their reuptake, some antidepressant drugs are also capable of decreasing NO levels (by an unknown mechanism), which could lead to further increases in serotonin levels in the brain. In agreement with that, antidepressants of different pharmacological classes are able to inhibit the function of the NMDA-NOS signaling pathway in vitro (Li et al 2006) and in vivo (Wegener et al 2003), making the inhibition of NO synthesis a central component of the behavioral effects induced by antidepressant drugs. This is further corroborated by the observation that discontinuation of an antidepressant treatment evoked a profound activation of hippocampal NOS activity accompanied by depressive-like behavior in the FST (Harvey et al 2006).…”

Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders

“…In this way, it has been demonstrated that inhibition of the NMDA-NO pathway appears to be one of the common actions of antidepressants. Despite remarkable structural diversity, three main kinds of antidepressants (desipramine, fluoxetine and moclobemide) not only antagonized the NMDAinduced lesion in PC12 cells, but also inhibited the function of the NMDA-NO signal pathway (22). These findings are consistent with the hypothesis first proposed by Paul and Skolnick (14) that clinically used antidepressants may share a common ability to block or down-regulate NMDA glutamate receptor function.…”

Protective Effects of Paeoniflorin Against Glutamate-Induced Neurotoxicity in PC12 Cells via Antioxidant Mechanisms and Ca2+ Antagonism

“…The rat adrenal pheochromocytoma (PC12) cell line, possessing typical features of neurons and expressing high level of glucocorticoid receptors (Gao et al 2009), has been widely used in a variety of studies. It has been reported that high concentration of glutamate could also induce neurotoxicity in PC12 cells (Penugonda et al 2005(Penugonda et al , 2006Li et al 2007;Yan et al 2009), while different types of classical antidepressants could protect against cytotoxicity induced by glutamate receptor in PC12 cells (Li et al 2006). These results suggest that cytoprotection against glutamate-induced neurotoxicity may represent one of the action pathways of antidepressants.…”