D-Cycloserine and estradiol enhance fear extinction in nulliparous but not primiparous female rats

Female reproductive experience has been shown to alter the hormonal, neurobiological and behavioural features of fear extinction, which is the laboratory basis of exposure therapy. This raises uncertainties as to whether pharmacological agents that enhance fear extinction in reproductively inexperienced females are equally effective in reproductively experienced females. The aim of the current study was therefore to compare the effects of two pharmacological enhancers of fear extinction, D-cycloserine (DCS) and estradiol, between nulliparous (virgin) and primiparous (reproductively experienced) female rats. In Experiment 1, nulliparous and primiparous females received systemic administration of either DCS or saline immediately after extinction training, and were tested for extinction recall the following day. DCS enhanced extinction recall in nulliparous females that showed low levels of freezing at the end of extinction training, but not among those that showed high levels of freezing at the end of extinction training. DCS did not enhance fear extinction in primiparous females, regardless of their level of freezing at the end of extinction training. In Experiment 2, nulliparous and primiparous female rats received systemic administration of either estradiol or vehicle prior to extinction training. Estradiol enhanced extinction recall among nulliparous females, but not primiparous females. Increasing the dose of estradiol administered prior to extinction training did not alter the outcomes in primiparous females (Experiment 3). Together, these findings suggest that reproductive status may be an important individual difference factor associated with the response to pharmacological modulators of extinction in rats. The implications of these findings for the pharmacological augmentation of exposure therapy in clinical populations are discussed.