Birth controlling your fears: The long-term effects of adolescent exposure to hormonal contraceptives on fear extinction in long-evans female rats

Abstract

The mechanisms involved in inhibiting fear to a threatening cue can be studied in the laboratory via fear extinction, which is a process thought to underpin the development and treatment of anxiety disorders. In adult female rats, fluctuating sex hormones across the estrous cycle modulate fear extinction, and suppressing sex hormones via hormonal contraceptives (HCs) impairs fear extinction. Despite high usage of HCs during adolescence, no research has examined HC effects on extinction during this developmental phase. In the current study, adolescent female rats (postnatal day 35) were administered a nine day treatment of one of two HC formulations: a high dose of levonorgestrel (LEV), or a lower dose of LEV combined with ethinyl estradiol (EE). Rats received fear conditioning, extinction training, and extinction retention, either across the last few days of HC exposure, or two weeks post HC-cessation as adults (postnatal day 58). In both adolescents and adults, LEV impaired extinction retention, but EE + LEV did not. Altogether, these findings provide evidence that LEV impairs extinction retention during adolescence, and that this impairing effect lasts beyond the cessation of LEV when exposure begins during adolescence. Both HC formulations suppressed endogenous sex hormones during HC exposure, and neither produced long-term effects on endogenous sex hormones two weeks post cessation, suggesting that suppression of endogenous hormones were not the sole mechanism for the impairing effects of LEV on extinction retention. Such findings may have implications for the potential impact of HC use during adolescence on the development and treatment of anxiety disorders.