Ketamine works faster as an antidepressant in females than in males, and this sex difference has been linked to ovarian hormones and faster metabolism in females. In adult female Wistar rats, blocking estrogen receptor alpha (ERα) with the antagonist MPP before a single antidepressant dose of ketamine did not prevent ketamine from reducing behavioral despair in the forced swim test. ERα antagonism and ketamine together showed a possible interaction on anxiety-like behaviors in the open field and elevated plus maze, but this effect was not statistically significant. Neither treatment affected fear memory. The results indicate that the sex-specific antidepressant effects of ketamine do not depend on ERα activity, though ERα may still influence anxiety-related brain circuits.
A single antidepressant dose of ketamine (10 mg/kg) given to adult Wistar rats partially impaired fear extinction when administered before fear acquisition or retrieval, but did not affect encoding or retrieval of cued fear or spatial memory. In the Morris Water Maze, ketamine facilitated memory modulation and reduced escape latency during the first day of reversal training when given before training or reversal sessions. The drug did not impair acquisition or retrieval processes in either implicit (fear) or explicit (spatial) memory tasks, but exerted opposing effects on memory modulation: disrupting fear extinction while facilitating reversal spatial learning.