Dihydrotestosterone regulation of stress-related behaviors in mice exposed to subchronic variable stress

Abstract

Androgen actions through androgen receptors have been shown to regulate stress-related behaviors. However, the role of androgen receptors in regulating stress-related behaviors under chronic stress conditions are unclear. To assess this, male C57BL/6 J mice were gonadectomized and given either a blank capsule or a capsule containing dihydrotestosterone (DHT), which preferentially binds the androgen receptor. Mice were then subjected to subchronic variable stress (SCVS) or control conditions prior to testing for stress-related behaviors. In the open field test, control DHT-treated mice showed a greater number of center entries when compared to control mice that received a blank capsule, indicating decreased anxiety-like behaviors. In the forced swim test, control mice receiving DHT spent less time floating compared to control mice that received a blank capsule, indicating a more active coping pattern in DHT-treated mice. However, these effects of DHT in the open field and forced swim tests were not observed in mice exposed to SCVS. Assessment of nest building, an assay of quality of daily living, revealed that DHT enhanced nest building in both control and SCVS conditions. No significant differences were found in the splash test, sucrose preference, or novelty suppressed feeding test. Analysis of c-Fos in mice exposed to forced swim revealed region-specific neural activation alterations by SCVS and DHT in the extended amygdala, nucleus accumbens, hippocampus, and prefrontal cortex. Together, these results suggest that androgen actions through androgen receptors reduce behavioral stress responses, although some protective effects may be lost following SCVS.

Keywords: Amygdala; Androgen; Androgen receptor; Anxiety; Depression; Dihydrotestosterone.