Nitrous oxide induces hypothermia and TrkB activation: Maintenance of body temperature abolishes antidepressant-like effects in mice.

Recent studies indicate that nitrous oxide (N ₂ O), a gaseous anesthetic and an NMDA (N-methyl-D-aspartate) receptor antagonist, produces rapid antidepressant effect in patients suffering from treatment-resistant depression. Our recent work implies that hypothermia and reduced energy expenditure are connected with antidepressant-induced activation of TrkB neurotrophin receptors - a key regulator of synaptic plasticity. In this study, we demonstrate that a brief exposure to N ₂ O leads to a drop in body temperature following the treatment, which is linked to decreased locomotor activity; enhanced slow-wave electroencephalographic activity; reduced brain glucose utilization; and increased phosphorylation of TrkB, GSK3β (glycogen synthase kinase 3β), and p70S6K (a kinase downstream of mTor (mammalian target of rapamycin)) in the medial prefrontal cortex of adult male mice. Moreover, preventing the hypothermic response in a chronic corticosterone stress model of depression attenuated the antidepressant-like behavioral effects of N ₂ O in the saccharin preference test. These findings indicate that N ₂ O treatment modulates TrkB signaling and related neurotrophic signaling pathways in a temperature-dependent manner, suggesting that the phenomenon driving TrkB activation - altered thermoregulation and energy expenditure - is linked to antidepressant-like behavioral responses.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Okko Alitalo reports financial support was provided by Instrumentarium Science Foundation. Okko Alitalo reports financial support was provided by University of Helsinki Doctoral Programme in Drug Research. Samuel Kohtala reports financial support was provided by Orion Research Fundation. Samuel Kohtala reports financial support was provided by Sigrid Jusélius Foundation. Samuel Kohtala reports financial support was provided by Finnish Cultural Foundation. Tomi Rantamaki reports financial support was provided by Research Council of Finland. Tomi Rantamaki reports financial support was provided by Sigrid Jusélius Foundation. Tomi Rantamaki reports financial support was provided by Business Finland. Tomi Rantamaki reports equipment, drugs, or supplies was provided by Oy Woikoski Ab. Marko Rosenholm reports financial support was provided by Finnish Cultural Foundation. Tomi Rantamäki reports financial support was provided by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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