Subanesthetic ketamine modulates region-specific neural and endocrine responses to acute stress in rats

Exposure to acute, inescapable stress triggers a coordinated neural and endocrine response across corticolimbic and brainstem circuits. Although subanesthetic ketamine has rapid antidepressant effects, it is unclear whether its modulation of the stress-response network depends on the presence of an acute stressor. In this study, naïve rats received subanesthetic ketamine (15 mg/kg) or a vehicle, and then underwent the tail suspension test (TST) or remained undisturbed in their home cages. Ketamine reduced immobility in the TST and attenuated the stress-induced increase in plasma corticosterone levels. Regional c-Fos expression, ascertained through quantitative real-time PCR and immunohistochemistry, revealed region-specific and context-dependent modulation. Ketamine selectively activated neuronal populations in the prefrontal cortex and potentiated stress-induced activation in the hippocampus and dorsal raphe nucleus. However, it suppressed stress-driven hyperactivation in the amygdala and elicited non-additive activation patterns in the brainstem. These findings suggest that subanesthetic ketamine modulates the regional balance of neuronal activation and attenuates hypothalamic-pituitary-adrenal axis reactivity in a state-dependent manner. Furthermore, its effects on the stress-response network are influenced by the presence of an acute stressor.