LPS inhibits the effects of fluoxetine on depression-like behavior and hippocampal neurogenesis in rats

Depressed patients with increased inflammatory cytokines in peripheral blood have been reported to be more likely to exhibit treatment resistance. However, it is unknown whether the inflammation influences the action of antidepressant drugs. Here, we investigated the influence of lipopolysaccharide (LPS) on the antidepressant action of fluoxetine in depressive rats induced by chronic unpredictable mild stress (CUMS). In this study, we first modified the CUMS paradigm by administration of LPS daily before the stressor, and then investigated the influence of inflammation on the antidepressant action of fluoxetine. The effects of stress exposure and antidepressant treatment were assessed by behavioral testing (sucrose preference test, forced swimming test, novelty suppressed feeding test) and hippocampal BrdU labeling. The CUMS-induced behavioral changes can be reversed by 4-week fluoxetine treatment. Fluoxetine also increased the hippocampal neurogenesis in the depressive rats. Pretreatment with LPS, to mimic inflammation, had no significant effect on depressive behavior but attenuated the antidepressant action of fluoxetine significantly. Thus, our results suggest that the inflammation might play a certain role in the pathophysiology of antidepressant treatment resistance.