Objective: Predator stress, social defeat stress, and fear conditioning animal models have been applied to investigate combat-related posttraumatic stress disorder (PTSD). However, no animal model psychopharmacological studies have investigated prevention of somatization of increased mental stress and fatigue at the beginning of combat exposure. This study utilized a novel animal model simulating the beginning of combat exposure that aided specification of a set of biomarkers. Methods: Psychological stress was induced by both inescapable electric foot shock and noise stimuli. Physical fatigue was induced by sleep deprivation and forced exercise in a rotating cage. A new device reflecting simultaneous psychological stress and physical fatigue was constructed. The protocol simulating combat exposure was set as 3 rounds of 24-h exposure in a 2-week period, which was specified as intermittent unpredictable stress (IUS). Results: Mice exposed to IUS (IUS mice) had significantly higher serum corticosterone levels (p < 0.05), excessive locomotive activity (p < 0.001), and anxiety-like behavior (p < 0.02) compared to control mice. IUS mice also had significantly higher IFN-γ (p < 0.001) and TNF-α (p < 0.05) levels in the supernatant of splenic T-cell culture compared to control mice. Brain-derived neurotropic factor levels were significantly decreased (p < 0.04) after IUS exposure. Conclusion: The proposed animal model of combat exposure reflected cognitive function impairment, behavior disturbance, and altered neuroimmune interactions without any apparent histopathological changes, and this animal model may be more applicable to protective research on war syndrome than combat-related PTSD after war because the hypothalamic-pituitary-adrenal axis has not been blunted.

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