Inhibition of N-methyl-D-aspartate receptor function appears to be one of the common actions for antidepressants.
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.
Li
Yun-Feng
YF
Division of Psychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China. lyf619@yahoo.com.cn
Zhang
You-Zhi
YZ
Liu
Yan-Qin
YQ
Wang
Heng-Lin
HL
Cao
Jiang-Bei
JB
Guan
Ting-Ting
TT
Luo
Zhi-Pu
ZP
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003891:Desipramine / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020912:Moclobemide / Q000494:pharmacology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D016716:PC12 Cells; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles
D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D018691:Excitatory Amino Acid Antagonists; D008996:Monoamine Oxidase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D013778:Tetrazolium Salts; D013844:Thiazoles; D005473:Fluoxetine; D016202:N-Methylaspartate; D007770:L-Lactate Dehydrogenase; D052248:Nitric Oxide Synthase Type I; C022616:thiazolyl blue; D020912:Moclobemide; D002118:Calcium; D003891:Desipramine