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

Abstract

Number of words in the abstract: 227 (250 max)Number of words in the text: 3812 (4000 max) ABSTRACT 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 (2R,6R)hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-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 (2S,6S)-HNK, but not (2R,6R)-HNK, attenuated learned fear in male mice. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, significantly reduced stress-induced depressive-like behavior in male and female mice. (R,S)ketamine and (2R,6R)-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

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

“…Although the initial findings demonstrating antidepressant-relevant biological activity of ( 2R,6R )-HNK have been widely replicated and expanded upon by a number of independent research groups (Bonaventura et al, 2022; Cavalleri et al, 2018; Chen et al, 2018; Chou et al, 2018; Collo et al, 2018; Fred et al, 2019; Fukumoto et al, 2019; Pham et al, 2018; Wray et al, 2018; Yao et al, 2018; Ye et al, 2019), (2 R, 6 R )-HNK is one of the major brain metabolites of ( R,S )-ketamine, but its antidepressant-like activity and contribution to the actions of the parent drug has been contested (Abdallah, 2017; Collingridge et al, 2017; Zanos et al, 2017). We previously showed that a systemic or intra-cortical administration of ( 6 )-HNK displayed similar sustained antidepressant-like behavioral actions to those of ( R,S )-ketamine (i.e., at 24 hours post-injection (t24h)) when assessed using the forced swim test (FST).…”