Brain estrogen alters the effects of the antidepressant sertraline in middle-aged female and male mice

Estrogens are important in regulating mood, especially for females. However, whether tissue-specific estrogen, such as brain estrogen, contributes to the effects of antidepressant treatment has not been determined. The present study used middle-aged aromatase gene knockout (Ar-/-) mice or overexpression (Thy1-Ar; hGFAP-Ar) mice as brain estrogen models to investigate whether brain estrogen synthesis alters the anti-depressive behaviors of sertraline treatment. Our results showed that depletion of brain estrogen increased depressive-like behavior in females, and elevated brain estrogen reduced depression-like behavior, regardless of sex. These genotype-related behaviors correlated with alterations of monoamine metabolism in the hippocampus (HPC) and the prefrontal cortex (PFC). We also demonstrated that male and female Ar-/- mice exhibited an attenuation of sertraline-induced anti-depressive behaviors compared to wild-type (WT) mice. The present data suggest that brain estrogen alters depressive-like behaviors and changes the effectiveness of antidepressants in middle-aged mice, regardless of sex.