The effectiveness of (R)-ketamine and its mechanism of action differ from those of (S)-ketamine in a chronic unpredictable mild stress model of depression in C57BL/6J mice

(S)-ketamine has been approved as a rapid-acting antidepressant drug (RAAD). Although ketamine has an advantage over classic antidepressants (ADs) due to its rapid action, it remains a controversial drug due to its undesirable effects. Behavioral studies indicate that another enantiomer of ketamine, namely, (R)-ketamine, has been proposed as a safer but still effective RAAD. However, these conclusions have not been confirmed in any model of depression based on chronic environmental stress, which effectively reflects the core symptoms of this disease. Thus, we decided to compare the effects of (R)- and (S)-ketamine on chronic unpredictable mild stress (CUMS) in mice. Behavioral studies showed that (R)-ketamine induced anti-anhedonic and anti-apathetic efficacy up to seven days after administration, while the (S)-ketamine effect persisted up to 24 h or 3 days after injection. The behavioral effects of (R)-ketamine depended on the activation of TrkB receptors, while the (S)-ketamine effects did not. Western blot analyses showed that (S)-ketamine action might be related to both mTOR and ERK pathway activation and to the increased expression of GluA1 protein in the prefrontal cortex (PFC). In contrast, (R)-ketamine did not change ERK phosphorylation in the PFC, while it increased mTOR expression. (S)-Ketamine produced behavioral effects indicative of possible side effects in the dose range studied, while (R)-ketamine did not. This indicates that (R)-ketamine may be more effective, have a longer-lasting effect, and be safer to use than (S)-ketamine.