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

• Published in: Pharmacology, biochemistry and behavior Vol. 191; p. 172876
• Main Authors: Yokoyama, Rei, Higuchi, Momoko, Tanabe, Wataru, Tsukada, Shinji, Naito, Megumi, Yamaguchi, Takumi, Chen, Lu, Kasai, Atsushi, Seiriki, Kaoru, Nakazawa, Takanobu, Nakagawa, Shinsaku, Hashimoto, Kenji, Hashimoto, Hitoshi, Ago, Yukio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2020
• Subjects: Anhedonia - drug effects; Animals; Anti-anhedonic; Antidepressant; Antidepressive Agents - administration & dosage; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Behaviors; C57BL/6J mice; Corticosterone - administration & dosage; Corticosterone - pharmacology; Depression - chemically induced; Depression - drug therapy; Depression model; Disease Models, Animal; Female; Ketamine - administration & dosage; Ketamine - analogs & derivatives; Ketamine - pharmacology; Ketamine metabolites; Locomotion - drug effects; Male; Mice; Mice, Inbred C57BL; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Antidepressant; Anti-anhedonic; Behaviors; Ketamine metabolites; C57BL/6J mice; Depression model
• ISSN: 0091-3057; 1873-5177; 1873-5177
• DOI: 10.1016/j.pbb.2020.172876

Clinical 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 anhedonia at 24 h after the injection. These results suggest that (S)-ketamine metabolites (S)-NK and (2S,6S)-HNK have potent acute and sustained antidepressant effects in rodents. •Chronic corticosterone induced a depression-like state and anhedonia in mice.•No ketamine metabolite showed antidepressant effects in naïve C57BL/6J mice.•(S)-NK and (2S,6S)-HNK reversed the enhanced immobility in the forced swim test.•(S)-NK and (2S,6S)-HNK improved impaired female preferences.