Estradiol-induced enhancement of fear extinction in female rats: The role of NMDA receptor activation

Converging cross-species evidence indicates that fear extinction (the laboratory basis of exposure therapy for anxiety disorders) in females is modulated by endogenous and exogenous estradiol. The mechanisms underlying estradiol's influences on fear extinction are largely undefined. However, one likely candidate is the NMDA-receptor (NMDAr), activation of which is necessary for estradiol-mediated enhancements in structural and functional neural plasticity, as well as extinction consolidation in males. Here, we demonstrate that systemic co-administration of the non-competitive NMDAr antagonist, MK801, blocked the enhancement of fear extinction by systemic estradiol in ovariectomized rats. In intact rats, MK801 during diestrus (rising estradiol) prevented the enhancement in extinction recall in rats that received extinction training during proestrus (peak estradiol). Systemic administration of the partial NMDAr agonist D-cycloserine (DCS) prior to extinction training facilitated extinction in ovariectomized rats, mimicking the effects of estradiol. In intact rats, DCS administered on the afternoon of proestrus and the morning of estrus (declining estradiol) facilitated extinction in rats that received extinction training during metestrus (low estradiol). Finally, DCS also facilitated extinction in ovariectomized rats when administered immediately after extinction training. Combined, these findings suggest that endogenous and exogenous estradiol enhance fear extinction via NMDAr-dependent mechanisms. Moreover, these findings raise the possibility that fear extinction deficits during periods of low endogenous estradiol levels can be reversed by increasing NMDAr activation via DCS administration, either well prior to, or immediately after, extinction training.