The role of Fezolinetant in fear memory consolidation

Modulation of fear memories has important implications for the treatment of different psychiatric disorders including fear-based disorders such as posttraumatic stress disorder (PTSD). The Tachykinin2 (Tac2)/Neurokinin B (NkB)/neurokinin 3 receptor (NK3R) pathway is a potential candidate for treating fear-based disorders built on animal and human studies. Here we demonstrate that the NK3R Antagonist Fezolinetant presents sex-divergent effects in the processing of fear memories in mice exposed to cued-fear conditioning. Fezolinetant (1 and 10 mg/kg, intraperitoneally (i.p.)) administered 30 min after the fear acquisition impairs the fear memory consolidation in male mice, as measured by fear expression 24 h later, showing no effects in naturally cycling female mice, with no monitoring the estrous cycle. However, when the estrous cycle was monitored, Fezolinetant (1 and 10 mg/kg, i.p.) enhanced fear memory consolidation during the proestrus phase, which suggests an effect dependent on high levels of the sex Hormones estradiol and/or progesterone. Considering that Fezolinetant is currently a treatment for hot flashes in menopausal women, our results could be rapidly translated into clinical trials focused on treating or preventing fear-based disorders. Thus, these findings support the role of Tac2/NkB/NK3R in fear memory consolidation and emphasize the importance of considering sex differences in the neurobiology of memory-related processes.

Cued-fear conditioning; Memory processing; Proestrus; Sex differences.