(S)-norketamine and (2S,6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression

Publication date: Available online 20 February 2020Source: Pharmacology Biochemistry and BehaviorAuthor(s): Rei Yokoyama, Momoko Higuchi, Wataru Tanabe, Shinji Tsukada, Megumi Naito, Takumi Yamaguchi, Lu Chen, Atsushi Kasai, Kaoru Seiriki, Takanobu Nakazawa, Shinsaku Nakagawa, Kenji Hashimoto, Hitoshi Hashimoto, Yukio AgoAbstractClinical and preclinical studies have shown that the N-methyl-d-aspartate receptor antagonist ketamine exerts rapid and long-lasting antidepressant effects. Although ketamine metabolites might also have potential antidepressant properties, controversial results have been reported for (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in particular, and there is little information regarding the effects of other ketamine metabolites. Here we aimed to compare the effects of (R)-norketamine ((R)-NK), (S)-NK, (2R,6R)-HNK, and (2S,6S)-HNK in a mouse model of depression induced by chronic corticosterone (CORT) injection. None of the ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naïve male C57BL6/J mice. Chronic CORT treatment increased immobility in the forced swim test and caused anhedonic-like behaviors in the female encounter test. A single administration of (S)-NK and (2S,6S)-HNK dose-dependently reduced the enhanced immobility at 30 min after injection in chronic CORT-treated mice, while (R)-NK or (2R,6R)-HNK did not. Additionally, (S)-NK and (2S,6S)-HNK, but not (R)-NK or (2R,6R)-HNK, improved chronic CORT-induced anhed...
Source: Pharmacology Biochemistry and Behavior - Category: Biochemistry Source Type: research