Ketamine influences CLOCK:BMAL1 function leading to altered circadian gene expression.
Marina M Bellet, Marquis P Vawter, Blynn G. Bunney, William E. Bunney, Paolo Sassone-Corsi
PLoS One 2011 DOI: 10.1371/journal.pone.0023982 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro cell study Peer reviewed |
|---|---|
| Population | NG108-15 neuronal cells |
| Interventions | Ketamine SB21673 |
| Measures | chromatin immunoprecipitation |
| Topics | Esketamine Ketamine |
| Key points | Ketamine dose-dependently inhibits CLOCK:BMAL1-mediated transcriptional activation in NG108-15 neuronal cells, an effect attenuated by the GSK3β antagonist SB21673, and reduces the amplitude of circadian transcription of Bmal1, Per2, and Cry1. Chromatin immunoprecipitation showed ketamine alters CLOCK:BMAL1 recruitment to circadian promoters over time. The authors propose this as a previously unsuspected molecular mode of action that may suggest pharmacological antidepressant strategies. |
Abstract
Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.
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 12
- Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers Therapeutic Advances in Psychopharmacology 2020
- A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. Journal of Affective Disorders 2022
- Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice. Nature Communications August 23, 2024
- Neurobiological biomarkers of response to ketamine. Advances in pharmacology (San Diego, Calif.) 2020
- Do sleep changes mediate the anti‐depressive and anti‐suicidal response of intravenous ketamine in treatment‐resistant depression? Journal of Sleep Research June 16, 2021
and 7 more in the library
Cites 8
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Glutamatergic Modulators: The Future of Treating Mood Disorders? Harvard Review of Psychiatry August 1, 2010
- Rapid-acting antidepressant strategies: mechanisms of action The International Journal of Neuropsychopharmacology July 7, 2011
- Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Molecular Psychiatry April 19, 2011
and 3 more in the library