Comparable Acute Antidepressant-like Effects of Two Subanesthetic Ketamine Doses Are Associated with Divergent Region-Specific Molecular Responses After Adolescent Chronic Stress
Ana Zivanovic, Iva Lukic, Emilija Glavonic, Zeljka Brkic, Milos Mitic, Sanja Ivkovic, Miroslav Adzic
International Journal of Molecular Sciences October 15, 2026 DOI: 10.3390/ijms27209126 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled animal experiment Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice exposed to chronic unpredictable stress during adolescence and showing depression-like behavior in adulthood, plus non-stressed vehicle controls |
| Intervention | Ketamine |
| Dose | 6 or 10 mg/kg, single injection |
| Duration | Single injection; behavioral testing at 24 h and one week; molecular analyses 48 h after ketamine administration |
| Measures | Tail suspension test (TST) |
| Topics | Esketamine Ketamine |
| Key findings | Both 6 and 10 mg/kg ketamine reduced tail suspension test immobility 24 hours after a single injection, indicating comparable acute antidepressant-like effects, but the effect was not sustained one week later. The 10 mg/kg dose produced more extensive region-specific changes in ERK, mTOR, JNK, and BDNF signaling than 6 mg/kg without a greater behavioral effect, which the authors interpret as evidence that behavioral relevance depends on regional context rather than overall pathway activation magnitude. |
Abstract
Ketamine produces rapid antidepressant-like effects across a range of subanesthetic doses, yet how dose shapes behavioral efficacy and region-specific molecular signaling following adolescent chronic unpredictable stress (CUS) is not well understood. Here, we examined the behavioral and molecular consequences of two subanesthetic ketamine doses in adult mice with depression-like behavior induced by CUS. Male C57BL/6J mice were exposed to CUS during adolescence and developed depression-like behavior in adulthood. Adult mice received a single injection of vehicle or ketamine at 6 or 10 mg/kg, while non-stressed controls received vehicle. Both ketamine doses reduced immobility in the tail suspension test 24 h after treatment, indicating comparable acute antidepressant-like effects; however, this effect was not sustained one week later. Molecular analyses of the prefrontal cortex, hippocampus, and striatum were performed 24 h after behavioral testing, corresponding to 48 h after ketamine administration, to define region-specific ERK, mTOR, JNK, and BDNF signaling profiles. These analyses revealed dose- and region-dependent regulation of all four markers. The higher ketamine dose produced more extensive molecular changes without producing a greater reduction in tail-suspension test (TST) immobility, suggesting that the behavioral relevance of ketamine-induced signaling depends on regional context rather than the overall magnitude of pathway activation.
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 11
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R ,6 R )-hydroxynorketamine Proceedings of the National Academy of Sciences December 17, 2018
- Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
and 6 more in the library