Acute trazodone treatment ameliorates behavioral abnormalities and improves subsequent short‐term memory in a lipopolysaccharide‐induced mouse model of acute brain dysfunction

Abstract Aim Systemic inflammation‐associated acute brain dysfunction, typified by delirium, is linked to later cognitive impairment. Although trazodone is used clinically for delirium‐related symptoms, its effects on subsequent cognition remain unclear. We examined whether acute‐phase trazodone treatment influences behavioral abnormalities, later cognitive outcomes, and inflammatory/glial‐related changes in an lipopolysaccharide (LPS)‐induced mouse model. Methods Adult male C57BL/6J mice received saline or LPS (3.0 mg/kg, intraperitoneally). Control mice received saline, whereas LPS‐treated mice subsequently received saline or trazodone (10 mg/kg, subcutaneously). In addition to a group receiving trazodone during the acute phase (Days 0–2), a group receiving trazodone for 7 days was also included. Behavioral assessments were performed on Day 1 (acute phase), Day 3 (recovery phase), and Day 7 (postrecovery phase) using nesting, open‐field, Y‐maze, and novel object recognition tests. Plasma cytokines and inflammatory and glial markers in the cerebral cortex and hippocampus were also assessed. Results During the acute phase, trazodone‐treated LPS mice showed reduced locomotor activity, whereas stimulus‐dependent exploratory behavior and nesting were relatively preserved. During the recovery phase, novel object recognition performance was better in trazodone‐treated than in saline‐treated LPS mice. Elevations of cortical Iba1 and IL‐6 and hippocampal GFAP during the acute phase were evident in saline‐treated LPS mice but not clearly in trazodone‐treated LPS mice. Direct comparison between the two trazodone regimens showed no clear additional benefit of continued treatment. Conclusion In this model, acute‐phase trazodone treatment was associated with milder acute behavioral abnormalities and better subsequent short‐term‐memory performance, whereas the benefit of continued treatment remained uncertain.