A mouse model of oral contraceptive exposure: depression, motivation, and the stress response

Abstract

Hormonal contraceptives (HCs) regulate hormonal levels and cycles, and thereby affect many physiological outcomes including stress responsivity and acne. Many individuals also experience overall benefits in regulation of mood, yet up to 10% of HC users experience depression, anxiety, and other adverse events. Despite 60 years of availability, it remains unclear how HCs modulate brain, behavior, and mood. Here, we created and validated a mouse model of HC exposure to answer mechanistic questions arising from studies of human HC use. Young adult female C57Bl/6N mice received either daily oral hormone treatments or a control (10% sucrose) treatment to mimic daily oral contraceptive exposure in humans. Hormone treatments were a combination of ethinyl estradiol (EE) and a progestin—either levonorgestrel (LVNG) or drospirenone (DRSP)—in 10% sucrose. Translationally-relevant doses of EE+LVNG-exposure caused a specific anhedonia-like effect, without indication of broad depression- or anxiety-like presentations. EE+LVNG, but not EE+DRSP, suppressed the acute stress response, an effect consistent with that observed in human HC users. Importantly, the limited changes in behavioral outcomes, together with suppression of regular estrous cycling and suppression of the corticosterone response to acute stress demonstrate the validity and tractability of this model with which to investigate questions difficult to study in human subjects. Thus, this model will be important for identifying mechanisms and risks for adverse effects of HCs on mood that will contribute to a more personalized approach to HC prescribing strategies.