Biological variations in ketamine sensitivity: insights from hyperlocomotion to psychotomimetic features in genetically diverse mouse strains.
Wen-Huei Siao, Tzong-Shi Wang, Liang-Chun Wang, Mao-Liang Chen, Yi-Chyan Chen
Psychiatry Research April 1, 2026 DOI: 10.1016/j.psychres.2026.116995 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study Peer reviewed |
|---|---|
| Population | Adolescent male mice of four strains: C57BL/6J, DBA, BALB/c, and 129S1 |
| Intervention | Ketamine |
| Dose | 0, 25, or 50 mg/kg |
| Duration | 30 min baseline session, 60 min post-injection monitoring |
| Topics | Esketamine Ketamine |
| Keywords | Animal model Genetic diversity Ketamine sensitivity Nmda receptor hypofunction Schizophrenia |
| Key findings | Ketamine-induced locomotor activity varies by mouse strain and dose, with C57BL/6J mice showing robust hyperlocomotion, DBA mice transient excitation, BALB/c mice delayed excitation, and 129S1 mice minimal changes. |
Abstract
Ketamine, a non-competitive NMDA receptor antagonist, induces dissociative and psychotomimetic states and is widely used as an animal model for schizophrenia. However, strain-dependent variability in ketamine sensitivity is poorly understood, especially during adolescence, a developmental period marked by heightened vulnerability to NMDA receptor hypofunction. This study would compare differences in pharmacological susceptibility to ketamine among different mouse strains. The four mouse strains-C57BL/6 J, DBA, BALB/c, and 129S1-were acclimated during adolescence. A novel open-field test equipped with a video-tracking system was employed as the primary method to assess motor behavioral changes. Following a 30 min baseline free-running session, mice received intraperitoneal injections of ketamine at doses of 0, 25, or 50 mg/kg, and their activity was monitored for an additional 60 min. The results revealed distinct pharmacological reactions to ketamine, influenced by both dose and strain. Locomotor activity varied significantly among the four strains before and after ketamine treatment (p < 0.001), with activity levels ranked as follows: C57BL/6J > DBA = BALB/c > 129S1. Ketamine produced dose-dependent robust hyperlocomotion in C57BL/6 J mice, transient excitation in DBA mice at 25 mg/kg, and delayed excitation in BALB/c mice at 50 mg/kg. 129S1 mice showed minimal net changes across doses. The study findings highlight diverse neurobehavioral characteristics among different mouse strains, demonstrating that pharmacological responses to ketamine are modulated by both dose and genetic background. These results indicate variability in ketamine sensitivity across strains, which may be relevant for understanding individual differences in behavioral responses to ketamine during adolescence.
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 7
- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
- Reviewing the ketamine model for schizophrenia Journal of Psychopharmacology November 20, 2013
- Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia JAMA Network Open May 1, 2020
- N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry November 3, 2016
- Mouse strain differences in phencyclidine-induced behavioural changes. The International Journal of Neuropsychopharmacology July 1, 2012
and 2 more in the library