Repeated Nitrous Oxide Exposure Exerts Antidepressant-Like Effects Through Neuronal Nitric Oxide Synthase Activation...

Clinical studies have demonstrated that exposure to the inhalational general anesthetic nitrous oxide (N₂O) produces antidepressant effects in depressed patients. However, the mechanisms underlying the antidepressant effects of N₂O remain largely unknown. Neuronal nitric oxide synthase (nNOS)-mediated nitric oxide (NO) synthesis is essential for brain function and underlies the molecular mechanisms of many neuromodulators. We hypothesized that activation of the nNOS/NO pathway in the medial prefrontal cortex (mPFC) might mediate the antidepressant effects of N₂O. In this study, we revealed that repeated N₂O exposure produced antidepressant-like responses in mice. Our mechanistic exploration showed that repeated N₂O exposure increased burst firing activity and that the expression levels of BDNF with nNOS activation were dependent in the mPFC. In particular, the antidepressant-like effects of N₂O were also antagonized by local nNOS inhibition in the mPFC. In summary, our results indicated that N₂O exposure enhances BDNF expression levels and burst firing rates in an nNOS activation dependent manner, which might underlie the pharmacological mechanism of the antidepressant-like effects of N₂O exposure. The present study appears to provide further mechanistic evidence supporting the antidepressant effects of N₂O.