Biological variations in ketamine sensitivity: insights from hyperlocomotion to psychotomimetic features in genetically diverse mouse strains.

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.