Nature communications
August 23, 2024
David H Sarrazin, Wilf Gardner, Carole Marchese et al.
41 citations
Depression involves disrupted circadian rhythms, but the role of internal clocks in mood-regulating brain areas was unclear. In a mouse model of depression, the medial prefrontal cortex (mPFC) showed increased expression of circadian negative-loop genes and decreased positive-clock regulators, and the rapid antidepressant ketamine counteracted these changes. Removing the clock gene Bmal1 from excitatory neurons prevented both depression-like behavior and ketamine's effects. Silencing the clock gene Per2 in mPFC produced antidepressant-like effects, while activating REV-ERB worsened depression and blocked ketamine. Boosting the clock activator ROR had antidepressant-like effects, increasing plasticity-related proteins and synaptic receptors in mPFC. The mPFC molecular clock critically regulates depression-like behavior, and targeting it therapeutically may influence glutamatergic plasticity.
bioRxiv Preprint Server
September 19, 2022
Stanislav Rozov, Roosa Saarreharju, Stanislav Khirug et al.
preprint
Inhaling 50% nitrous oxide (laughing gas) for one hour and a single low dose of ketamine both alter gene expression in the medial prefrontal cortex of adult mice, particularly affecting regulators of MAPK signaling pathways in pyramidal cells. Nitrous oxide produced much broader and more widespread changes in mRNA expression than ketamine. However, unlike ketamine, nitrous oxide did not increase the firing rate of putative pyramidal neurons or boost gamma brain wave activity. The findings suggest that while both substances share some molecular effects, their neural activity patterns differ markedly.
Biology of Sex Differences
July 7, 2026
Gemma González-Hernández, S. Torres-Sánchez, D. Sanchez-Morillo et al.
Nitrous oxide (N₂O) at 50% concentration for one hour produced sex-specific effects on behavior and brain activity in mice with chronic pain. In males with neuropathic pain, N₂O reduced pain sensitivity, while females showed no pain relief. The drug decreased movement in both sexes, with longer-lasting effects in males. Brain recordings showed N₂O reduced low-frequency electrical activity in all mice, with stronger effects in females. In animals without pain, N₂O dampened brain responses to stimulation, but in pain-model mice it restored prefrontal activity. No antidepressant-like effects appeared 24 hours after treatment in either sex. These results indicate that N₂O's effects depend on sex and pain state, emphasizing the need to consider sex in NMDA receptor-based treatments.
Journal of neurophysiology
May 1, 2025
Petra Valtonen, Stanislav Rozov, Iina Annala et al.
Short-term administration of nitrous oxide (N2O) increases power in the theta frequency range (4-7 Hz) of the electroencephalogram (EEG) after the gas is withdrawn, but does not affect delta frequency (0.5-4 Hz) power. In a study of 14 healthy male participants, those receiving 50% N2O either continuously for 20 minutes or in two 10-minute inhalations showed rapid EEG transitions during gas administration and withdrawal. Power in high-frequency gamma bands increased during N2O, while beta and alpha frequencies decreased. After withdrawal, theta power increased in several electrodes, with negligible differences between the two treatment groups. The effect was reproducible with repeated dosing.
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.
European journal of pharmacology
April 5, 2024
Stanislav Rozov, Roosa Saarreharju, Stanislav Khirug et al.
Inhaling 50% nitrous oxide for one hour and a single low dose of ketamine both alter the activity of genes that regulate mitogen-activated protein kinases in the medial prefrontal cortex of adult mice, particularly in pyramidal cells. Nitrous oxide produced much larger and more widespread changes in gene expression than ketamine. Ketamine increased the firing rate of putative pyramidal neurons and boosted gamma brain wave activity, whereas nitrous oxide did not. The findings suggest that the two drugs share a common molecular target but cause different immediate electrical changes in the brain.
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.
Cell and tissue research
July 1, 2019
Tomi Rantamäki
Brain-derived neurotrophic factor (BDNF) and its receptor TrkB have been studied for decades in mood disorders and their treatments. Various antidepressant drugs increase BDNF synthesis in the cortex, promoting neurotrophic processes and heightened plasticity. Induction of BDNF-TrkB signaling is also linked to ketamine and some anesthetics, even those without known antidepressant effects. Both ketamine and conventional antidepressants rapidly activate TrkB receptor signaling in the brain, while electroconvulsive therapy (ECT), a potent BDNF inducer, has not been clearly shown to produce such acute TrkB effects. Antidepressant regulation of TrkB signaling is developmentally regulated and requires an intact central nervous system. This review highlights peculiarities in how ketamine, classical antidepressants, and BDNF affect TrkB signaling.
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.