Ketamine metabolite (2R,6R)-hydroxynorketamine reverses behavioral despair produced by adolescent trauma

Early life trauma dramatically increases the risk of developing major depressive disorder (MDD), and is associated with a markedly decreased adult treatment response to antidepressants. Novel treatment approaches are required to treat childhood trauma-associated MDD. Recent studies suggest that the (R,S)-ketamine (ketamine) metabolite, (2R,6R)-hydroxynorketamine (HNK), exerts fast- and long-lasting antidepressant-like effects without ketamine's NMDAR-inhibition-associated adverse side-effect profile. We investigated the therapeutic potential of (2R,6R)-HNK against behavioral despair produced by a novel live-predator stress exposure during adolescence. Male and female C57BL/6J mice were exposed to a live snake or control conditions at post-natal (PND) days 31, 45 and 61. In order to assess the enduring consequences of trauma-exposure, at a minimum of 14 days following the last exposure, mice received inescapable shocks followed by a session with available escape options twenty-four hours later. Mice that manifested enduring escape deficits (helplessness) were treated with vehicle or (2R,6R)-HNK (20 mg/kg, i.p.), 24 h prior to retesting for reversal of escape deficits. We found that a significantly greater number of mice developed the helpless phenotype when they were exposed to the live predator and that the helpless phenotype was reversed in mice treated with (2R,6R)-HNK. There were no sex differences in the response to predator-stress exposure or (2R,6R)-HNK treatment. The live-predator model developed in this study provides an opportunity to further refine our understanding of the neurobiological substrates impacted by adolescent trauma and improve treatment strategies. The demonstrated efficacy of (2R,6R)-HNK in this model suggests a novel therapeutic intervention for a treatment-resistant population.