Posttraumatic stress disorder (PTSD) is characterized by impaired fear extinction, and estradiol has been implicated in modulating extinction memory in a sex-dependent manner. Studies of classical estrogen receptors support a role for ER𝛽 in these effects. However, the contribution of the G protein-coupled estrogen receptor (GPER) remains unclear. This study investigated whether GPER activation enhances fear extinction memory consolidation in male and female rats. We hypothesized that 150uL/kg G1 would improve extinction memory in males, that females would benefit from all doses, and we expected increased phosphorylated extracellular signal-related kinase (pERK) in the amygdala of rats administered G1.

Rats underwent a three-day fear conditioning, extinction, and recall paradigm. Following extinction, they received a subcutaneous injection of GPER agonist G1 (15, 75, or 150µL/kg) or vehicle (sesame oil). Freezing during recall assessed extinction retention. Immunohistochemistry was performed on tissue collected after recall to investigate amygdalar pERK expression.

Preliminary results suggest GPER activation improves extinction retention in females in a dose-dependent manner. In males, the lowest and middle doses enhance retention, but not the highest dose. Comparisons between males and females receiving equivalent doses revealed no sex differences in extinction retention. Analysis of amygdalar pERK expression showed no relationship between ERK and GPER activation. These findings suggest that post-extinction GPER activation enhances fear extinction memory in both sexes through mechanisms not reflected in amygdalar ERK phosphorylation. Further investigation with larger sample sizes and brain regions will define a role for estrogen receptor mechanisms in estrogen’s action on fear behavior.