Nitric Oxide Synthase inhibition counteracts the stress‐induced DNA methyltransferase 3b expression in the hippocampus of rats

It has been postulated that the activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr‐induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress‐induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed an increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre‐treatment with nNOS inhibitor nω‐propyl‐l‐arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7‐NI and aminoguanidine (AMG) decreased the number of escape failures in LH and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus. Stress mediators such as excessive activation of NMDA or glucocorticoid receptors increased the DNMT3b mRNA expression in the hippocampus of rats submitted to the learned helplessness paradigm. The antidepressant‐like effect of NOS inhibitors was associated with attenuation of the DNMT3b expression. The NOS activity participates in the cellular pathways related to DNA methylation triggered by unpredictable and uncontrollable stress.