Lack of metabolism in (R)-ketamine’s antidepressant actions in a chronic social defeat stress model

Since the metabolism of (R,S)-ketamine to (2R,6R)-hydroxynorketamine (HNK) is reported to be essential for ketamine’s antidepressant effects, there is an increasing debate about antidepressant effects of (2R,6R)-HNK. Using pharmacokinetic and behavioral techniques, we investigated whether intracerebroventricular (i.c.v.) infusion of (R)-ketamine or (2R,6R)-HNK show antidepressant effects in a chronic social defeat stress (CSDS) model of depression. Low levels of (2R,6R)-HNK in the brain after i.c.v. infusion of (R)-ketamine were detected, although brain levels of (2R,6R)-HNK were markedly lower than those after i.c.v. infusion of (2R,6R)-HNK. Furthermore, high levels of (2R,6R)-HNK in the blood and liver after i.c.v. infusion of (R)-ketamine or (2R,6R)-HNK were detected. A single i.c.v. infusion of (R)-ketamine showed rapid and long-lasting (7 days) antidepressant effects in a CSDS model. In contrast, i.c.v. infusion of (2R,6R)-HNK did not show any antidepressant effect in the same model, although brain concentration of (2R,6R)-HNK was higher than after i.c.v. infusion of (R)-ketamine. This study suggest that (R)-ketamine in the periphery after washout from the brain is metabolized to (2R,6R)-HNK in the liver, and subsequently, (2R,6R)-HNK enters into brain tissues. Furthermore, it is unlikely that (2R,6R)-HNK is essential for the antidepressant actions of (R)-ketamine in a CSDS model.