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

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.