Acute ketamine treatment produces long-term anxiolytic effects despite increasing oxidative stress in female Wistar Kyoto rats

Treatment-resistant depression and anxiety remain major challenges in psychiatry, particularly in female patients, who are disproportionately affected yet remain underrepresented in preclinical ketamine research. The present study investigated short- and long-term anxiolytic effects of acute subanesthetic ketamine administration in female Wistar-Kyoto (WKY) rats, a validated genetic model of treatment-resistant affective dysfunction. Subjects received a single intraperitoneal injection of saline vehicle or racemic ketamine (5, 10, or 15 mg/kg), followed by acoustic startle response (ASR) testing 24 hours and 7 days later. Oxidative stress was assessed using 8-oxo-2'-deoxyguanosine (8-oxo-dG) immunofluorescence in the basolateral amygdala (BLA), prefrontal cortex (PFC), and hippocampus, alongside analysis of parvalbumin-positive (PV+) interneurons. Ketamine treatment produced dose- and time-dependent behavioral effects with 10 mg/kg eliciting the strongest delayed anxiolytic-like response at 7 days, while 15 mg/kg showed more immediate behavioral effects at 24 hours. While ketamine did not alter PV+ cell count, it significantly increased oxidative stress markers globally in the BLA and prelimbic region of the PFC and specifically in the PV+ interneurons in the BLA. The findings suggest that ketamine's therapeutic effects in female WKY rats may involve region-specific modulation of stress circuitry and oxidative signaling rather than gross interneuron loss. Overall, the study provides evidence for sex-dependent and temporally dynamic effects of ketamine in a translational model of treatment-resistant anxiety and depression.