Ketamine decreases HPA axis reactivity to a novel stressor in male but not female mice
Colin J. Johnston, Paul J. Fitzgerald, Jena S. Gewarges, Brendon O. Watson, Joanna L. Spencer-Segal
bioRxiv Preprint Server June 29, 2021 preprint DOI: 10.1101/2021.06.29.450387 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Male and female C57BL/6J mice |
| Interventions | Ketamine Metyrapone |
| Dose | 30 mg/kg, i.p. (ketamine); 20 mg/kg, i.p. (metyrapone) |
| Duration | One and two days after injection for behavioral tests |
| Topics | Ketamine Esketamine |
| Keywords | Antidepressant Drug Medication Sex differences Sex-specific effects Gender differences Male vs female Sexual dimorphism Stress response Stress hormones Stress reduction Physiological stress |
| Citations | 5 |
| Key findings | Ketamine after chronic stress decreases the corticosterone response to a novel stressor in male mice but not in females. |
Abstract
Ketamine is an antidepressant drug that interacts with the hypothalamic-pituitary-adrenal (HPA) axis, but whether this interaction is important for its behavioral effect is unknown. The goal of this experiment was to determine whether the behavioral response to ketamine depends on intact HPA axis function. Male and female C57BL/6J mice underwent chronic unpredictable stress prior to ketamine (30 mg/kg, i.p.) or vehicle treatment, with or without the glucocorticoid synthesis inhibitor metyrapone (20 mg/kg, i.p.) to block adrenal corticosterone production. Mice were tested in the forced swim test (FST) and open field test one and two days after injection, respectively. Fecal corticosterone was measured at select time points. No significant drug effects on behavior were observed. Males consistently had higher fecal corticosterone levels and stress-induced increases than females. Ketamine lowered the fecal corticosterone response to the FST only in males. These data show that ketamine after chronic stress decreases the corticosterone response to a novel stressor (the FST) in males, but not females. Corticosterone levels in all mice correlated with immobility in the FST, suggesting that shared neural circuitry could mediate both endocrine and behavioral responses. This circuitry may be ketamine-responsive only in males.
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 3
- Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigation Neurobiology of Stress April 20, 2022
- Subanesthetic ketamine modulates region-specific neural and endocrine responses to acute stress in rats. Neuropharmacology October 19, 2026
- The Glutamatergic System in Treatment-Resistant Depression and Comparative Effectiveness of Ketamine and Esketamine: Role of Inflammation? Advances in experimental medicine and biology 2023
Cites 7
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Ketamine – More mechanisms of action than just NMDA blockade Trends in Anaesthesia and Critical Care March 22, 2014
- Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions Proceedings of the National Academy of Sciences June 8, 2015
- A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Anesthesiology October 1, 2011
and 2 more in the library