Ketamine's acute effects on TrkB-GSK3β signaling in the mouse cortex are not limited to subanesthetic (antidepressant) doses; sedative or anesthetic doses produce more prominent increases in slow EEG oscillations and phosphorylation of TrkBY816 and GSK3βS9. A sedative dose of 6,6-d2-ketamine (100 mg/kg) recapitulated these effects, while cis-HNK (20 mg/kg) produced negligible acute effects on this signaling or slow oscillations. The findings indicate that the molecular mechanisms associated with ketamine's antidepressant actions are not exclusively triggered by low doses and that cis-HNK is not responsible for these acute signaling changes.
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NMDA receptors, produces rapid antidepressant effects in animals through a mechanism that emerges after the drug is withdrawn, not during its peak action.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.