Diverse Modulatory Effects of Sex Steroids on Depressive-Like Behavior in Socially Stressed Female Rats

Objective: The role of sex steroids in mammals extends beyond the conventional influence on the reproductive system. Sex hormones have been shown to modulate cognitive performance and emotionality in animal models and humans. This study used a model of social stress to induce depressive-like behavior in females at all stages of the estrous cycle. Method: The social interaction test, sucrose splash test, and sucrose preference test were used to study depressive-like behavior induced by social isolation at different estrous cycle phases. Furthermore, animals were treated with estradiol, progesterone, and antagonists of both hormones, tamoxifen and mifepristone. Results: Our main findings showed that (a) depressive-like behavior induced by social isolation was estrous cycle-dependent, (b) females in diestrus had higher depressive-like behavior, (c) stressed females treated with estradiol (but not progesterone) showed less depressive-like behavior, and (d) tamoxifen-treated stressed females in proestrus had an increase in depressive-like behaviors. Conclusions: These findings indicate that endogenous changes of sex hormones modulate depressive-like behavior in socially isolated females. Taken together, the diverse impact of estradiol and progesterone-based on the specific activity of the respective antagonists-points to a differential relevance of these sex hormones on mood disorders. Public Significance Statement Hormones connected to the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonadal axes can interact and influence affective-like behaviors. However, the neurological basis of the role of these hormones in depressive illnesses caused by chronic stress is still debated, in part due to a lack of studies that include females in their experimental protocols. This study suggests that endogenous fluctuations in estrogen levels across the estrous cycle affect depressive-like behaviors triggered by social isolation. Estradiol had a beneficial effect on depressive-like behaviors, which was counteracted by prior exogenous administration of the antagonist tamoxifen. Furthermore, neither progesterone nor mifepristone caused significant changes.