Estrogen receptor alpha (ERα) partially modulates ketamine's sustained anxiolytic effects without altering its antidepressant properties in female rats

Abstract

Ketamine is a rapid-acting antidepressant with sexually dimorphic effects. Female animals exhibit a higher sensitivity to its antidepressant properties, which has been associated with their ovarian hormone levels. One factor contributing to this sex difference is the faster rate of ketamine metabolism observed in females, potentially regulated by estrogen receptor alpha (ERα) through modulation of enzymatic activity. In this study, we explored the role of ERα in mediating the therapeutic effects of ketamine in adult female Wistar rats. To inhibit ERα, we administered its antagonist, methyl-piperidino-pyrazole (MPP; 1 mg/kg, IP), 24 h and 1 h prior to a single antidepressant dose of ketamine (10 mg/kg, IP) or saline (vehicle). We tested the animals in the forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and auditory fear conditioning. Ketamine administration ameliorated behavioral despair observed in the vehicle group, and ERα antagonism did not affect this outcome. An interaction between MPP and ketamine was observed in anxiety-like behaviors assessed in the OFT and EPM; however, this effect did not reach significance in post-hoc analyses. Neither MPP nor ketamine affected fear memory, as measured in cued fear conditioning. These findings suggest that the sexually dimorphic antidepressant effects of ketamine occur independently of ERα activity, although ERα may influence neural circuits related to anxiety.