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

Abstract

Hormonal contraceptives, including oral contraceptives (OCs), regulate hormonal cycles and broadly affect physiological processes, including stress responsivity. Whereas many users describe overall improved mood, up to 10 % of OC users experience adverse effects, including depression and anxiety. Given the link between regulation of hypothalamic-pituitary-adrenal (HPA) axis, stress exposure, and risk for depression, it is likely that OC-effects on stress mediate increased risk or increased resilience to these disorders. In this study, we developed and characterized a tractable mouse model of OC exposure with which to identify the mechanisms underlying OC modulation of brain, behavior, and mood. Specifically, we aimed to determine whether translationally relevant doses of OC-hormones in mice mimic changes in stress responsivity observed in humans taking OCs and describe behavioral changes during OC exposure. Young adult female C57Bl/6 N mice received daily ethinyl estradiol (EE) and levonorgestrel (LVNG) in 10 % sucrose, EE and drospirenone (DRSP) in 10 % sucrose, or 10 % sucrose alone. Translationally relevant doses of EE + LVNG-exposure, but not EE + DRSP, suppressed the acute stress response, consistent with effects observed in human OC users. EE + LVNG caused a specific anhedonia-like effect, without broad changes in stress-coping behavior, other depression-like behaviors, or anxiety-like behaviors. The suppression of regular estrous cycling, together with the blunting of the corticosterone response to acute stress, demonstrate the utility of this model for future studies to identify the mechanisms underlying OC interactions with stress, motivation, and risk for depression.

Keywords: Anhedonia; Depression; Estrous; Ethinyl estradiol; Hormone contraceptives; Levonorgestrel; Motivation; Risk-assessment; Stress; Stress-coping.