Aim:To explore the mechanism of agmatine’s antidepressant action.Methods:Male mice were subjected to a variety of unpredictable stressors on a daily basisover a 24-d period.The open-field behaviors of the mice were displayed andrecorded using a Videomex-V image analytic system automatically.For bromodeo-xyuridine(BrdU;thymidine analog as a marker for dividing cells)labeling,the micewere injected with BrdU(100 mg/kg,ip,twice per d for 2 d),and the hippocampalneurogenesis in stressed mice was measured by immunohistochemistry.Theproliferation of cultured hippocampal progenitor cells from neonatal rats wasdetermined by colorimetric assay(cell counting kit-8)and ~3H-thymidine incorpo-ration assay.Results:After the onset of chronic stress,the locomotor activity ofthe mice in the open field significantly decreased,while coadministration of agma-tine 10 mg/kg(po)blocked it.Furthermore,the number of BrdU-labeled cells in thehippocampal dentate gyrus significantly decreased in chronically stressed mice,which was also blocked by chronic coadministration with agmatine 10 mg/kg(po).Four weeks after the BrdU injection,some of the new born cells matured andbecame neurons,as determined by double labeling for BrdU and neuron specificenolase(NSE),a marker for mature neurons.In vitro treatment with agmatine 0.1-10 μmol/L for 3 d significantly increased the proliferation of the cultured hippoc-ampal progenitor cells in a dose-dependent manner.Conclusion:We have foundthat agmatine increases proliferation of hippocampal progenitor cells in vitro andthe hippocampal neurogenesis in vivo in chronically stressed mice,This may beone of the important mechanisms involved in agmatine’s antidepressant action. Aim: To explore the mechanism of agmatine’s antidepressant action. Methods: Male mice were subjected to a variety of unpredictable stressors on a daily basis over a 24-d period. The open-field behaviors of the mice were displayed andrecorded using a Videomex-V image analytic system automatically.For bromodeo-xyuridine (BrdU; thymidine analog as a marker for dividing cells) labeling, the mice were injected with BrdU (100 mg / kg, ip, twice per d for 2 d), and the hippocampal neurogenesis in stressed mice was measured by immunohistochemistry. The proliferation of cultured hippocampal progenitor cells from neonatal rats was determined by colorimetric assay (cell counting kit-8) and ~ 3H-thymidine incorpo-ration assay. Results: After the onset of chronic stress, the locomotor activity of the mice in the open field significantly decreased, while coadministration of agma-tine 10 mg / kg (po) blocked it.Furthermore, the number of BrdU-labeled cells in thehippocampal dentate gyrus significantly decreased in chronically stre ssed mice, which was also blocked by chronic coadministration with agmatine 10 mg / kg (po). Fours weeks after the BrdU injection, some of the new born cells matured andbecame neurons, as determined by double labeling for BrdU and neuron specificenolase (NSE) , a marker for mature neurons. In vitro treatment with agmatine 0.1-10 μmol / L for 3 d significantly increased the proliferation of the cultured hippoc-ampal progenitor cells in a dose-dependent manner. Conclusion: We have found that agmatine increases proliferation of hippocampal progenitor cells in vitro and the hippocampal neurogenesis in vivo in chronically stressed mice, This may be of the important mechanisms involved in agmatine’s antidepressant action.