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The molecular mechanisms underlying the behavioral effects of glucocorticoids are poorly understood.We report here that hippocampal neuronal nitric oxide synthase (nNOS) is a crucial mediator.Chronic mild stress and glucocorticoids exposures caused hippocampal nNOS overexpression via activating mineralocorticoid receptor (MR).In turn, hippocampal nNOS-derived nitric oxide (NO) significantly down-regulated local glucocorticoid receptor (GR) expression through both soluble guanylate cyclase (sGC)/cGMP and peroxynitrite (ONOO-)/extracellular signal-regulated kinase (ERK) signal pathways, and thence elevated hypothalamic corticotrophin-releasing factor (CRF), a peptide that governs the hypothalamic-pituitary-adrenal axis.More importantly, nNOS deletion or intrahippocampal nNOS inhibition and NO-cGMP signaling blockade (using NO scavenger or sGC inhibitor) prevented the corticosterone-induced behavioral modifications, suggesting that hippocampal nNOS is necessary for the role of glucocorticoids in mediating depressive behaviors.In addition, directly delivering ONOO-donor into hippocampus caused depressive-like behaviors.Our findings reveal a role of hippocampal nNOS in regulating the behavioral effects of glucocorticoids.