Acute ketamine treatment produces long-term anxiolytic effects despite increasing oxidative stress in female Wistar Kyoto rats
Alena Lemeshova, Feysal Abdirahaman, Haney Haidari, Cherish Zhao, Aiman Limbada, Jennifer A. Honeycutt
bioRxiv July 1, 2026 preprint DOI: 10.64898/2026.06.26.734907 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study |
|---|---|
| Population | Female Wistar-Kyoto (WKY) rats, a genetic model of treatment-resistant affective dysfunction |
| Interventions | Racemic ketamine saline vehicle |
| Dose | 5, 10, or 15 mg/kg, single intraperitoneal injection |
| Duration | Behavioral testing at 24 hours and 7 days after injection |
| Measures | Acoustic startle response (ASR), 8-oxo-2'-deoxyguanosine (8-oxo-dG) immunofluorescence, parvalbumin-positive (PV+) interneuron analysis |
| Topics | Esketamine Ketamine |
| Key findings | A single ketamine injection in female WKY rats produced dose- and time-dependent anxiolytic-like behavioral effects, with 10 mg/kg strongest at 7 days and 15 mg/kg more immediate at 24 hours. Ketamine did not alter parvalbumin-positive cell counts but increased oxidative stress markers in the basolateral amygdala and prelimbic prefrontal cortex, including within amygdala parvalbumin interneurons. The authors suggest these effects involve region-specific modulation of stress circuitry and oxidative signaling rather than gross interneuron loss. |
Abstract
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.
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 |