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.
Basic & clinical pharmacology & toxicology
August 1, 2021
Samuel Kohtala, Tomi Rantamäki
Ketamine's rapid antidepressant effects are linked to increased glutamate signaling and synaptic plasticity in the prefrontal cortex, with activation of the BDNF receptor TrkB as a key event. The mechanisms behind ketamine's effects on TrkB remain unclear. Nitrous oxide, another rapid antidepressant, activates TrkB signaling after its acute effects have faded, coinciding with increased slow delta frequency EEG activity. Various anesthetics and sedatives also activate TrkB signaling, suggesting that rapid-acting antidepressants may share the ability to regulate TrkB during homeostatically evoked slow-wave activity, which may be important for sustained antidepressant effects. This work urges examining brain physiology and temporally distributed signaling patterns beyond conventional receptor pharmacology.
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, Puja K Parekh, Iman Baramaki et al.
preprint
A single 50% nitrous oxide treatment rapidly increases neuronal calcium activity in the mouse medial prefrontal cortex, elevates c-Fos expression, and enhances wake-associated gamma oscillations and slow-wave activity during sleep, indicating cortical activation and synaptic potentiation. In a chronic corticosterone stress model, nitrous oxide produced antidepressant-like behavioral effects in several but not all domains. These actions parallel key effects of subanesthetic ketamine.
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.