Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

BACKGROUND Females are more likely than males to develop major depressive disorder (MDD) after exposure to stress. We previously reported that the administration of ( R,S )-ketamine before stress can prevent stress-induced depressive-like behavior in male mice but have yet to assess efficacy in female mice or for other compounds, such as the metabolites of ( R,S )-ketamine. METHODS We administered ( R,S )-ketamine or its metabolites (2 R ,6 R )-hydroxynorketamine ((2 R ,6 R )-HNK) and (2 S ,6 S )-HNK at various doses 1 week before one of a number of stressors, including contextual fear conditioning (CFC), learned helplessness (LH), and chronic immobilization stress (CIS), in male and female 129S6/SvEv mice. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy surgery (OVX) and a hormone replacement protocol prior to drug administration. RESULTS ( R,S )-ketamine and (2 S ,6 S )-HNK, but not (2 R ,6 R )-HNK, attenuated learned fear in male mice. ( R,S )-ketamine and (2 R ,6 R )-HNK, but not (2 S ,6 S )-HNK, significantly reduced stress-induced depressive-like behavior in male and female mice. ( R,S )-ketamine and (2 R ,6 R )-HNK) were prophylactically effective at a lower dose (10 mg/kg and 0.025 mg/kg, respectively) in female mice than in male mice (30 mg/kg and 0.075 mg/kg, respectively). Moreover, ovarian-derived hormones were necessary and sufficient for prophylaxis in female mice. CONCLUSIONS Our results suggest that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and that ovarian hormones mediate prophylactic efficacy in females. To our knowledge, this is the first demonstration of the prophylactic efficacy of the metabolites of ( R,S )-ketamine in male and female mice.