Dehydroepiandrosterone-sulfate did not mitigate sickness behavior in mice

In response to lipopolysaccharide (LPS), macrophages secrete cytokines that transmit a message to the brain and induce sickness behavior. Because dehydroepiandrosterone (DHEA) and its sulfated ester (DHEA-S) reportedly improve mental health and modulate cytokine production, we hypothesized that DHEA-S administration would inhibit LPS-induced sickness behavior. Mice were provided drinking water with 0% or 0.01% DHEA-S for 2 weeks and then injected intraperitoneally with saline or LPS (1 μg). Sickness behavior was quantified using a social investigation paradigm, and DHEA-S in plasma and brain was determined at the study's end. DHEA-S did not affect water intake, food intake, or body weight during the 2-week period. As anticipated, LPS depressed social behavior. The maximum depression was observed 2 h postinjection, after which social investigation steadily increased until returning to baseline level at 8 h. DHEA-S did not mitigate the effects of LPS on social behavior even though DHEA-S in plasma and brain was increased 150- and 6-fold, respectively, in mice given DHEA-S. In a separate study, mice were given DHEA-S for 3 months and then challenged with LPS. Consistent with the first study, LPS reduced social behavior irrespective of DHEA-S treatment. However, 3 months administration of DHEA-S reduced the depression from baseline after injection of saline or LPS. DHEA-S in plasma and brain for mice given DHEA-S for 3 months was similar to that observed after 2 weeks. Collectively, these results suggest that DHEA-S has neuromodulatory effects but is ineffective at ameliorating LPS-induced sickness behavior.