(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

A single subanesthetic infusion of ketamine can rapidly alleviate symptoms of treatment-resistant major depression. Since repeated administration is required to sustain symptom remission, it is important to characterize the potential untoward effects of prolonged ketamine exposure. While studies suggest that ketamine can alter cognitive function, it is unclear to what extent these effects are modulated by the frequency or chronicity of treatment. To test this, male and female adolescent (postnatal day [PD] 35) and adult (PD 60) BALB/c mice were treated for four consecutive weeks, either daily or thrice-weekly, with (R,S)-ketamine (30 mg/kg, intraperitoneal) or its biologically active metabolite, (2R,6R)-hydroxynorketamine (HNK; 30 mg/kg, intraperitoneal). Following drug cessation, memory performance was assessed in three operationally distinct tasks: (1) novel object recognition to assess explicit memory, (2) Y-maze to assess working memory, and (3) passive avoidance to assess implicit memory. While drug exposure did not influence working memory performance, thrice-weekly ketamine and daily (2R,6R)-HNK led to explicit memory impairment in novel object recognition independent of sex or age of exposure. Daily (2R,6R)-HNK impaired implicit memory in the passive-avoidance task whereas thrice-weekly (2R,6R)-HNK tended to improve it. These differential effects on explicit and implicit memory possibly reflect the unique mechanisms by which ketamine and (2R,6R)-HNK alter the functional integrity of neural circuits that subserve these distinct cognitive domains, a topic of clinical and mechanistic relevance to their antidepressant actions. Our findings also provide additional support for the importance of dosing frequency in establishing the cognitive effects of repeated ketamine exposure.