Neuropharmacology
December 15, 2024
Okko Alitalo, Samuel Kohtala, Marko Rosenholm et al.
A brief exposure to nitrous oxide (N2O) causes a drop in body temperature, reduced movement, enhanced slow-wave brain activity, decreased brain glucose use, and increased phosphorylation of TrkB, GSK3β, and p70S6K in the medial prefrontal cortex of adult male mice. Preventing the hypothermic response in a chronic stress model of depression weakened the antidepressant-like behavioral effects of N2O in the saccharin preference test. These findings indicate that N2O treatment modulates TrkB signaling and related neurotrophic pathways in a temperature-dependent manner, linking altered thermoregulation and energy expenditure to antidepressant-like behavioral responses.
bioRxiv
August 31, 2021
O. Alitalo, S. Kohtala, Marko Rosenholm et al.
preprint
Both pharmacological and non-pharmacological treatments for depression activate TrkB receptors—a known antidepressant target—by inducing a physiological response linked to sedation. Rapid-acting antidepressants trigger TrkB signaling by evoking a state characterized by electroencephalographic slow-wave activity, behavioral immobility, reduced cerebral glucose utilization, and lowered body temperature. This signaling was not impaired in animals with reduced activity-dependent BDNF release but was diminished by maintaining animals in a warm ambient temperature. Preventing the hypothermic response attenuated the behavioral effects of the rapid-acting antidepressant nitrous oxide. The findings suggest that changes in energy expenditure and thermoregulation are essential, but not sufficient, for antidepressant responses, challenging pharmacology-centric hypotheses and highlighting the role of bioenergetics and thermoregulation.
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.