Estradiol and Progesterone have Opposing Roles in the Regulation of Fear Extinction in Female Rats

Fear extinction, the laboratory basis of exposure therapy for anxiety disorders, fluctuates across the female rat estrous cycle, where extinction is enhanced during proestrus (high estradiol and progesterone), and impaired during metestrus (low estradiol and progesterone). During the estrous cycle increasing levels of estradiol precede and then overlap with increased levels of progesterone. We sought to isolate the impact of these hormonal changes on fear extinction by systematically treating ovariectomized female rats with estradiol alone, or in combination with progesterone. We found that estradiol alone facilitated extinction recall, whereas the effects of progesterone on estradiol-treated rats were biphasic and dependent on the time interval between progesterone administration and extinction training. Progesterone potentiated estradiol's facilitation of extinction recall when extinction training occurred 6 h after progesterone administration. However, progesterone abolished estradiol's facilitation of extinction recall when extinction training occurred 24 h after progesterone administration. Furthermore, in naturally cycling rats, blocking progesterone receptor activation during proestrus (when progesterone levels peak) prevented the impairment in extinction recall in rats extinguished during metestrus. These results suggest that in naturally cycling females whereas cyclical increases in estradiol facilitate fear extinction, cyclical increases in progesterone may lead to fear extinction impairments. As extinction training took place after the hormonal treatments had been metabolized, we propose that genomic mechanisms may at least partly mediate the impact of cyclic fluctuations in sex hormones on fear extinction.