Putative rapid-acting antidepressant nitrous oxide (“laughing gas”) evokes rebound emergence of slow EEG oscillations during which TrkB signaling is induced

Nitrous oxide (laughing gas), a dissociative anesthetic that blocks NMDA receptors, produces rapid antidepressant effects in animals through a mechanism that emerges after the drug is withdrawn, not during its peak action. The gas induces rebound slow EEG oscillations, a brain state also seen with ketamine and electroconvulsive therapy, that is characterized by sedation and drowsiness. During this withdrawal phase, signaling changes in TrkB and GSK3β proteins gradually appear, suggesting that the antidepressant effect relies on cortical excitability triggered by the drug's offset rather than its acute presence.

Study at a glance

Abstract

Abstract Electroconvulsive therapy (ECT) remains among the most efficient antidepressants but it seldom brings immediate remedy. However, a subanesthetic dose of NMDA-R (N-methyl-D-aspartate receptor) blocker ketamine ameliorates symptoms of depression already within hours. Glutamatergic excitability and regulation of TrkB neurotrophin receptor and GSK3β (glycogen synthase kinase 3β) signaling are considered as molecular-level determinants for ketamine’s antidepressant effects. Recent clinical observations suggests that nitrous oxide (N 2 O, “laughing gas”), another NMDA-R blocking dissociative anesthestic, also produces rapid antidepressant effects but the underlying mechanisms remain essentially unstudied. In this animal study we show that N 2 O, with a clinically relevant dosing regimen, evokes an emergence of rebound slow EEG (electroencephalogram) oscillations, a phenomenon considered to predict the efficacy and onset-of-action ECT. Very similar rebound slow oscillations are induced by subanesthetic ketamine and flurothyl (a treatment analogous to ECT). These responses become best evident upon drug withdrawal, i.e. after the peak of acute pharmacological actions, when their most prominent effects on cortical excitability have subsided. Most importantly, TrkB and GSK3β signaling remain unchanged during N 2 O administration (ongoing NMDA-R blockade) but emerge gradually upon gas withdrawal along with increased slow EEG oscillations. Collectively these findings reveal that rapid-acting antidepressants produce cortical excitability that triggers “a brain state” dominated by ongoing slow oscillations, sedation and drowsiness during which TrkB and GSK3β signaling alterations are induced.