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bioRxiv · 10.1101/2025.02.13.638096

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

Kohtala, S.·Parekh, P. K.·Baramaki, I.·Kohtala, P.·Ilkka, L.·Antila, H.·Lee, F. S.·Liston, C.
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Abstract

Emerging evidence suggests that nitrous oxide (N2O), 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% N2O/O2 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 N2O 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, N2O elicited antidepressant-like behavioral effects in several, though not all, domains. Together, these findings indicate that a single treatment with N2O rapidly enhances cortical activity, modulates sleep and wake EEG oscillations, and produces antidepressant-like effects, paralleling key actions associated with subanesthetic ketamine.

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Kohtala, S., Parekh, P. K., Baramaki, I., Kohtala, P., Ilkka, L., Antila, H., Lee, F. S., Liston, C.. 2025-02-14. Nitrous oxide modulates cortical activity, wake-sleep oscillations, and produces antidepressant-like effects in mice. https://doi.org/10.1101/2025.02.13.638096

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