Sub-anesthetic and anesthetic ketamine produce different long-lasting behavioral phenotypes (24 h post-treatment) via inducing different brain-derived neurotrophic factor (BDNF) expression level in the hippocampus.
Chunhui Wu, Yu Wang, Yang He, Song Wu, Zhifei Xie, Jian Zhang, Jing-Shan Shen, Zhen Wang, Ling He
Neurobiology of Learning and Memory December 5, 2019 DOI: 10.1016/j.nlm.2019.107136 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine ANA-12 |
| Dose | sub-anesthetic dose; anesthetic dose |
| Duration | 24 hours after treatment |
| Topics | Esketamine Ketamine |
| Key points | Sub-anesthetic ketamine increased hippocampal BDNF and produced antidepressant and anxiolytic effects at 24 hours in mice, whereas anesthetic ketamine reduced BDNF and produced depressive-like behavior, anxiety-like behavior, and cognitive impairment. The TrkB inhibitor ANA-12 prevented the antidepressant effects of sub-anesthetic ketamine, leading the authors to conclude that BDNF may be the key factor underlying these effects. |
Abstract
Clinical and preclinical researches have shown that sub-anesthetic ketamine elicits sustained antidepressant effects for up to 1-2 weeks. Pharmacokinetics studies (t1/2 = 23 min) in mice showed no ketamine residue at 24 h after sub-anesthetic or anesthetic ketamine administration. Therefore, this study aims to reveal the mechanism underlying these different biological functions at 24 h after sub-anesthetic and anesthetic ketamine treatment. First, at the animal behavioral level, we found that sub-anesthetic ketamine induced antidepressant and anxiolytic effects while anesthetic ketamine induced depressive-like phenotypes and cognitive impairment. Second, we examined the correlation between behavior phenotype and protein expression, and found that the Brain-derived neurotrophic factor (BDNF) level is oppositely regulated by sub-anesthetic and anesthetic ketamine. Sub-anesthetic ketamine significantly increased the BDNF level, correlating to antidepressant effects; whereas anesthetic dose reduced BDNF expression in the hippocampus, correlating to depressive-like behaviors, anxiety-like behaviors and cognitive impairment. Third, the antidepressant effects of sub-anesthetic ketamine were prevented by pre-treatment of ANA-12, a Tropomyosin receptor kinase B (TrkB) inhibitor. Thus, we conclude that BDNF may be the key factor underlying antidepressant and anxiolytic effects of sub-anesthetic ketamine at 24 h after treatment. These results may shed light on future studies and the development of long-lasting anti-depressant drugs and therapies.
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 15
- Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers Therapeutic Advances in Psychopharmacology 2020
- Rapid-acting antidepressant drugs modulate affective bias in rats Science Translational Medicine January 10, 2024
- Partial mGlu5 receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice. Pharmacological Reports June 1, 2024
- Towards an expanded neurocognitive account of ketamine's rapid antidepressant effects. The International Journal of Neuropsychopharmacology February 4, 2025
- Cannabidiol reverses myeloperoxidase hyperactivity in the prefrontal cortex and striatum, and reduces protein carbonyls in the hippocampus in a ketamine-induced schizophrenia rat model. Schizophrenia Research April 1, 2025
and 10 more in the library
Cites 16
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- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study Biological Psychiatry November 4, 2015
and 11 more in the library