Neuropharmacology
October 1, 2019
Samuel Kohtala, Wiebke Theilmann, Marko Rosenholm et al.
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.
Molecular neurobiology
June 1, 2019
Samuel Kohtala, Wiebke Theilmann, Marko Rosenholm et al.
The antidepressant effects of NMDA receptor blockers like ketamine and nitrous oxide (laughing gas) become apparent only after their acute psychoactive effects wear off. In mice, nitrous oxide exposure initially increased markers of neuronal excitability, but regulation of the BDNF receptor TrkB and GSK3β signaling occurred gradually after drug discontinuation, during a brain state dominated by slow EEG activity. Subanesthetic ketamine and seizure-inducing flurothyl also produced slow oscillations after their acute effects subsided. A sedative that directly induces slow oscillations did not increase neuronal excitability markers or produce antidepressant-like behavior, suggesting that transient cortical excitability followed by homeostatic slow oscillations and TrkB-GSK3β signaling are critical for rapid antidepressant responses.
Samuel Kohtala, Wiebke Theilmann, Marko Rosenholm et al.
preprint
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NMDA receptors, produces rapid antidepressant effects in animals through a mechanism that emerges after the drug is withdrawn, not during its peak action.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.