慢性コルチコステロン投与によるマウスうつ様行動に対するケタミン代謝物の異なる作用

• Published in: 日本薬理学会年会要旨集 p. 3-P-288
• Main Authors: 横山, 玲, 樋口, 桃子, 塚田, 信司, 笠井, 淳司, 中澤, 敬信, 吾郷, 由希夫, 田邊, 航, 勢力, 薫, 橋本, 謙二, 橋本, 均
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2020
• Subjects: antidepressant; behavior; metabolism; N-methyl-D-aspartate (NMDA) receptor
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.93.0_3-P-288

Clinical and preclinical studies have shown that the NMDA receptor antagonist ketamine exerts rapid and long-lasting antidepressant effects. Although ketamine metabolites might also have potential antidepressant properties, controversial results have been reported on (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in particular and there is little information on 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 these 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 (R)-ketamine, but not an SSRI fluoxetine, showed antidepressant-like activity in chronic CORT-treated mice. (S)-NK and (2S,6S)-HNK dose-dependently reduced the increased immobility at 30 min after injection, while (R)-NK or (2R,6R)-HNK did not. Additionally, (S)-NK and (2S,6S)-HNK improved anhedonic-like behaviors at 24 h after injection. These results suggest that (S)-ketamine metabolites (S)-NK and (2S,6S)-HNK have potent acute and sustained antidepressant effects.