Subanesthetic ketamine modulates region-specific neural and endocrine responses to acute stress in rats.
U S Drozd, V V Bulygina, G T Shishkina, T S Kalinina, N N Dygalo, D A Lanshakov
Neuropharmacology October 19, 2026 DOI: 10.1016/j.neuropharm.2026.111231 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experimental animal study Peer reviewed |
|---|---|
| Population | Naïve rats |
| Intervention | Ketamine |
| Dose | 15 mg/kg |
| Measures | Tail suspension test (TST), plasma corticosterone levels, c-Fos expression (quantitative real-time PCR and immunohistochemistry) |
| Topics | Ketamine Esketamine |
| Keywords | Antidepressant-like effect Corticosterone Dorsal raphe nucleus Hpa axis Hippocampus Immediate-early gene Neuronal activation Prefrontal cortex Satb2 Tail suspension test Acute stress C-fos |
| Key findings | Subanesthetic ketamine (15 mg/kg) reduced immobility in the tail suspension test and attenuated the stress-induced increase in plasma corticosterone. c-Fos mapping showed context-dependent effects: ketamine activated prefrontal cortex neurons, potentiated stress-induced activation in the hippocampus and dorsal raphe nucleus, and suppressed stress-driven hyperactivation in the amygdala. The authors suggest ketamine modulates the regional balance of neuronal activation and HPA-axis reactivity in a state-dependent manner. |
Abstract
Exposure to acute, inescapable stress triggers a coordinated neural and endocrine response across corticolimbic and brainstem circuits. Although subanesthetic ketamine has rapid antidepressant effects, it is unclear whether its modulation of the stress-response network depends on the presence of an acute stressor. In this study, naïve rats received subanesthetic ketamine (15 mg/kg) or a vehicle, and then underwent the tail suspension test (TST) or remained undisturbed in their home cages. Ketamine reduced immobility in the TST and attenuated the stress-induced increase in plasma corticosterone levels. Regional c-Fos expression, ascertained through quantitative real-time PCR and immunohistochemistry, revealed region-specific and context-dependent modulation. Ketamine selectively activated neuronal populations in the prefrontal cortex and potentiated stress-induced activation in the hippocampus and dorsal raphe nucleus. However, it suppressed stress-driven hyperactivation in the amygdala and elicited non-additive activation patterns in the brainstem. These findings suggest that subanesthetic ketamine modulates the regional balance of neuronal activation and attenuates hypothalamic-pituitary-adrenal axis reactivity in a state-dependent manner. Furthermore, its effects on the stress-response network are influenced by the presence of an acute stressor.
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
Cites 19
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics TIPS - Trends in Pharmacological Sciences September 24, 2021
- Brain region-specific action of ketamine as a rapid antidepressant. Science August 9, 2024
- Transient Elevation of Plasma Glucocorticoids Supports Psilocybin-Induced Anxiolysis in Mice ACS Pharmacology & Translational Science August 2, 2023
and 14 more in the library