Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test
P. Fitzgerald, Jessica Yen, B. Watson
PLoS One April 15, 2019 DOI: 10.1371/journal.pone.0215554 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Reverse translational study Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice |
| Intervention | Ketamine |
| Dose | 10 mg/kg or 30 mg/kg |
| Duration | 24 hours and 7 days post-injection for forced swim test; open field test on day 8 |
| Topics | Esketamine Ketamine |
| Key points | Ketamine produces antidepressant-like effects in stressed mice but opposite effects in unstressed mice, indicating that stress modulates ketamine's behavioral effects. |
Abstract
Major depression is a stress-linked disease with significant morbidity and the anesthetic drug ketamine is of growing interest in the treatment of depression, since in responsive individuals a single dose has rapid (within hours) antidepressant effects that can be sustained for over a week in some instances. This combination of fast action and a therapeutic effect that lasts far beyond the drug’s half-life points to a unique mechanism of action. In this reverse translational study, we investigate the degree to which ketamine counteracts stress-related depression-like behavioral responses by determining whether it affects unstressed animals similarly to stressed mice. To test this, male C57BL/6J mice were given a single injection of vehicle (0.9% saline; i.p.), 10 mg/kg ketamine, or 30 mg/kg ketamine, and were tested in the forced swim test (FST) 24 hours and 7 days later, as well as in the open field test on the eighth day. Unstressed mice had normal group housing, environmental enrichment, and experimenter pre-handling (5 days), whereas stressed animals were subjected to chronic mild stress (single housing, reduced enrichment and minimal handling), where some mice also had daily two-week unpredictable chronic stress (UCS). We find that ketamine (24 hours post-injection) decreases immobility and increases mobile (swimming) behavior (antidepressant-like effects) in UCS animals but does the opposite in unstressed mice, similar to recent human findings. In summary, these data suggest that chronic psychological stress interacts with ketamine treatment to modulate its effects in the C57BL/6J mouse FST, which reinforces the relevance of this test, and this strain of mice, to human, stress-induced depression.
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 29
- Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice Nature Communications May 12, 2022
- Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology July 24, 2023
- Rodent ketamine depression-related research: Finding patterns in a literature of variability Behavioural Brain Research August 13, 2019
- Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine. Journal of Affective Disorders March 15, 2025
- Novel rapid treatment options for adolescent depression. Pharmacological Research March 1, 2024
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Cites 10
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine Has Distinct Electrophysiological and Behavioral Effects in Depressed and Healthy Subjects Molecular Psychiatry February 27, 2018
- Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine The International Journal of Neuropsychopharmacology October 7, 2016
- Long-Lasting Antidepressant Action of Ketamine, but Not Glycogen Synthase Kinase-3 Inhibitor SB216763, in the Chronic Mild Stress Model of Mice PLoS One February 4, 2013
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