Ketamine-induced regulation of TrkB-GSK3β signaling is accompanied by slow EEG oscillations and sedation but is independent of hydroxynorketamine metabolites.
Samuel Kohtala, Wiebke Theilmann, Marko Rosenholm, Heidi K Müller, Paula Kiuru, Gregers Wegener, Jari Yli-Kauhaluoma, Tomi Rantamäki
Neuropharmacology October 1, 2019 DOI: 10.1016/j.neuropharm.2019.107684 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Adult mouse cortex |
| Interventions | Ketamine 6 6-d2-ketamine cis-HNK |
| Dose | 10 mg/kg, >50 mg/kg, 100 mg/kg, 20 mg/kg |
| Topics | Ketamine Esketamine |
| Keywords | Anesthesia Antidepressant Sedation Slow oscillations Synaptosomes |
| Key findings | Ketamine dose-dependently increased slow oscillations and TrkB-GSK3β phosphorylation, with sedative/anesthetic doses (>50 mg/kg) producing more prominent effects than a subanesthetic dose (10 mg/kg), and cis-HNK had negligible acute effects on these measures. |
Abstract
Subanesthetic rather than anesthetic doses are thought to bring the rapid antidepressant effects of the NMDAR (N-methyl-d-aspartate receptor) antagonist ketamine. Among molecular mechanisms, activation of BDNF receptor TrkB along with the inhibition of GSK3β (glycogen synthase kinase 3β) are considered as critical molecular level determinants for ketamine's antidepressant effects. Hydroxynorketamines (2R,6R)-HNK and (2S,6S)-HNK), non-anesthetic metabolites of ketamine, have been proposed to govern the therapeutic effects of ketamine through a mechanism not involving NMDARs. However, we have shown that nitrous oxide, another NMDAR blocking anesthetic and a putative rapid-acting antidepressant, evokes TrkB-GSK3β signaling alterations during rebound slow EEG (electroencephalogram) oscillations. We investigated here the acute effects of ketamine, 6,6-d2-ketamine (a ketamine analogue resistant to metabolism) and cis-HNK that contains (2R,6R) and (2S,6S) enantiomers in 1:1 ratio, on TrkB-GSK3β signaling and concomitant electroencephalographic (EEG) alterations in the adult mouse cortex. Ketamine dose-dependently increased slow oscillations and phosphorylations of TrkBY816 and GSK3βS9 in crude brain homogenates (i.e. sedative/anesthetic doses (>50 mg/kg, i.p.) produced more prominent effects than a subanesthetic dose (10 mg/kg, i.p.)). Similar, albeit less obvious, effects were seen in crude synaptosomes. A sedative dose of 6,6-d2-ketamine (100 mg/kg, i.p.) recapitulated the effects of ketamine on TrkB and GSK3β phosphorylation while cis-HNK at a dose of 20 mg/kg produced negligible acute effects on TrkB-GSK3β signaling or slow oscillations. These findings suggest that the acute effects of ketamine on TrkB-GSK3β signaling are by no means restricted to subanesthetic (i.e. antidepressant) doses and that cis-HNK is not responsible for these effects.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 11
- Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
- Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice. Nature Communications August 23, 2024
- [Interest and mechanisms of action of ketamine in alcohol addiction- A review of clinical and preclinical studies]. Biologie aujourd'hui 2023
- Differential effects of ketamine enantiomers on EEG parameters including the gamma-delta shift phenomenon. British Journal of Pharmacology June 1, 2026
- Ketamine—50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms Pharmacological Reports February 20, 2021
and 6 more in the library
Cites 25
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD) Molecular Psychiatry October 3, 2018
and 20 more in the library