Nitrous oxide modulates cortical activity, wake–sleep oscillations, and produces antidepressant-like effects in mice

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Summary Emerging evidence suggests that nitrous oxide (N 2 O), a gaseous NMDA receptor antagonist and dissociative anesthetic, exerts rapid antidepressant effects akin to subanesthetic ketamine. However, its cellular, molecular, and behavioral effects remain poorly understood. Using in vivo two-photon imaging through cortical microprisms, we demonstrate that 50% N 2 O/O 2 rapidly increases neuronal calcium activity in the mouse medial prefrontal cortex (mPFC). This was corroborated by elevated c-Fos expression at both protein and mRNA levels in mPFC lysates. Cortical EEG recordings revealed that N 2 O increased subsequent wake-associated gamma oscillations and enhanced slow-wave activity during sleep, suggestive of cortical activation and synaptic potentiation. In a chronic corticosterone stress model, N 2 O elicited antidepressant-like behavioral effects in several, though not all, domains. Together, these findings indicate that a single treatment with N 2 O rapidly enhances cortical activity, modulates sleep and wake EEG oscillations, and produces antidepressant-like effects, paralleling key actions associated with subanesthetic ketamine.