Nitrous oxide induces prominent cell proliferation in adult rat hippocampal dentate gyrus

The identification of distinct and more efficacious antidepressant treatments is highly needed. Nitrous oxide (N₂O) is an N-methyl-D-aspartic acid (NMDA) antagonist that has been reported to exhibit antidepressant effects in treatment-resistant depression (TRD) patients. Yet, no studies have investigated the effects of sub-anesthetic dosages of N₂O on hippocampal cell proliferation and neurogenesis in adult brain rats. In our study, adult male Sprague-Dawley rats were exposed to single or multiple exposures to mixtures of 70% N₂O and 30% oxygen (O₂). Sham groups were exposed to 30% O₂ and the control groups to atmospheric air. Hippocampal cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation, and BrdU-positive cells were counted in the dentate gyrus (DG) using confocal microscopy. Results showed that while the rates of hippocampal cell proliferation were comparable between the N₂O and sham groups at day 1, levels increased by 1.4 folds at day 7 after one session exposure to N₂O. Multiple N₂O exposures significantly increased the rate of hippocampal cell proliferation to two folds. Therefore, sub-anesthetic doses of N₂O, similar to ketamine, increase hippocampal cell proliferation, suggesting that there will ultimately be an increase in neurogenesis. Future studies should investigate added N₂O exposures and their antidepressant behavioral correlates.