Ketamine, a non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, is widely used in general anesthesia and pain management. Recent studies have highlighted its efficacy in treating refractory depression and its anti-suicidal effects (Mion and Villevieille, 2013). However, ketamine is also a well-known recreational drug, particularly among adolescents. Beyond its psychedelic effects, users experience psychotomimetic symptoms such as perceptual distortion, perplexity, and psychotic behaviors (Frohlich and Van Horn, 2014; Lin et al., 2016; Mion and Villevieille, 2013). Ketamine-induced acute psychosis has been considered a model for schizophrenia in the glutamate hypothesis (Carlsson et al., 2004; Frohlich and Van Horn, 2014), as NMDA receptor-mediated signal transmission disruption leads to glutamatergic hypofunction and inhibition of γ-aminobutyric acid (GABA) neurotransmission. An imbalance between NMDA and GABA activity may result in dopaminergic hyperfunction, contributing to psychotomimetic symptoms (Becker et al., 2003; Carlsson et al., 2004; Frohlich and Van Horn, 2014; Zunszain et al., 2013). Additionally, ketamine induces schizophrenia-like behaviors, including negative symptoms (Carlsson et al., 2004; Chindo et al., 2012; Frohlich and Van Horn, 2014) and cognitive deficits (Lahti et al., 2001; Lee and Zhou, 2019; Mion and Villevieille, 2013). Sub-chronic ketamine use has also been linked to altered gene expression of dopamine and serotonin receptors (Chatterjee et al., 2011).

Biological variation is a fundamental concept integrated across various fields to shape research outcomes. Investigating behavioral differences among mouse strains helps identify variability in drug responsiveness and can inform future studies of the biological factors underlying drug actions. In addition, such comparisons may provide indirect insight into how drugs affect populations with distinct biological characteristics. A previous study found that individuals dependent on different substances exhibit diverse neuropsychological functions and behavioral traits, which may serve as preexisting factors influencing their choice of substances (Wang et al., 2017). Human studies have also identified biological variations in ketamine sensitivity, including the brain-derived neurotrophic factor (BDNF) genotype, which is associated with greater sensitivity to its antidepressant effects (Chen et al., 2021). Conversely, individuals more vulnerable to ketamine's psychotic side effects have also been identified (Beck et al., 2020; Honey et al., 2008). However, research on specific genotypes or endophenotypes related to ketamine-induced psychosis remains limited, particularly in adolescents and children due to ethical concerns.

Adolescence is a critical and challenging stage marked by significant biological and hormonal changes. The maturation of the brain—encompassing alterations in myelin sheath development, dendritic differentiation, and synaptic pruning and remodeling—is thought to play a key role in the onset of major psychiatric disorders, including schizophrenia (Hoffman and Dobscha, 1989; Sakai, 2020), and drug addiction (Andersen, 2019; Jordan and Andersen, 2017). These changes may also heighten susceptibility to both the acute and long-term negative effects of substance use. The extent to which certain individuals are more sensitive to ketamine’s effects and prone to developing psychotomimetic characteristics following acute use remains a topic of debate. Animal models provide a valuable approach to mimicking neuropsychiatric symptoms and exploring neurobehavioral differences following drug administration (Chen and Holmes, 2009; Deutsch et al., 1997; Mouri et al., 2012; Sarter and Bruno, 2003). Rodent studies commonly use the C57BL/6 J strain as the standard model for pre-clinical drug discovery, ensuring well-controlled conditions that simplify diverse clinical manifestations. To assess neuropharmacological variations in response to acute ketamine administration, we conducted a neurobehavioral study using four mouse strains (C57BL/6 J, DBA, BALB/c, and 129S1). Using a novel open-field test, we evaluated neurobehavioral changes in adolescent mice from each strain following treatment with varying doses of ketamine.