Abstract
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.
Highlights
Major depressive disorder (MDD) is one of the most severe mental disorders in the world and accounts for most of the nonfatal burden of mental and substance use disorders [1]
The results showed that both repeated N2O exposure, and ketamine treatments significantly reduced the immobility duration in the Forced Swim Test (FST) and TST compared with those of the control and vehicle groups [Figure 1B, one-way ANOVA, F [3, 34] = 2.896, p = 0.049; Figure 1C, one-way ANOVA, F [3, 33] = 2.923, p = 0.048]
The results showed that N2O exposure didn’t further increase BDNF levels in the medial prefrontal cortex (mPFC) when that region was pre-treated with L-NAME [Figures 3C–E, two-way ANOVA, F
Summary
Major depressive disorder (MDD) is one of the most severe mental disorders in the world and accounts for most of the nonfatal burden of mental and substance use disorders [1]. The currently the available antidepressants mostly target the monoaminergic system, but these classic antidepressants are associated with low remission rates and a lag in the onset of antidepressant action obtained [2,3,4], Nitrous Oxide Exerts Antidepressant-Like Effects highlighting an urgent and clear need for identifying a more efficacious and faster-acting therapeutic agents. Studies on the antidepressant effects of anesthetics have attracted considerable attention. Recent studies have suggested that some anesthetics show promise as therapeutics against MDD. Ketamine has attracted keen interest due to its remarkably rapid and sustained antidepressant effects [5,6,7]. When administrated as a single intravenous dose, ketamine is associated with some unwanted side effects, including dissociation, headache, dizziness, elevated blood pressure, and blurred vision [8]. The safety concerns of ketamine should be carefully considered, after repeated dosing
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