Journal
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
Volume 191, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbb.2020.172876
Keywords
Ketamine metabolites; Depression model; Antidepressant; Anti-anhedonic; Behaviors; C57BL/6J mice
Funding
- JSPS KAKENHI [JP15H04645, JP18H02574, JP17K19488, JP17H03989, JP16K08268]
- MEXT KAKENHI [JP19H04909, JP19H05218, JP18H05416]
- AMED [JP19gm1310003, JP19dm0107122, JP19dm0207061, JP19dm0107119]
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Pharmacological Research Foundation, Tokyo
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Clinical and preclinical studies have shown that the N-methyl-u-aspartate receptor antagonist ketamine exerts rapid and long-lasting anti-depressant 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 (COAT) injection. None of the ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naive male C57BL6/J mice. Chronic COAT 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.
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