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Using pharmacokinetic and behavioral techniques, we investigated whether intracerebroventricular (i.c.v.) infusion of (<jats:italic>R<\/jats:italic>)-ketamine or (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK show antidepressant effects in a chronic social defeat stress (CSDS) model of depression. Low levels of (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK in the brain after i.c.v. infusion of (<jats:italic>R<\/jats:italic>)-ketamine were detected, although brain levels of (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK were markedly lower than those after i.c.v. infusion of (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK. Furthermore, high levels of (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK in the blood and liver after i.c.v. infusion of (<jats:italic>R<\/jats:italic>)-ketamine or (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK were detected. A single i.c.v. infusion of (<jats:italic>R<\/jats:italic>)-ketamine showed rapid and long-lasting (7 days) antidepressant effects in a CSDS model. In contrast, i.c.v. infusion of (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK did not show any antidepressant effect in the same model, although brain concentration of (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK was higher than after i.c.v. infusion of (<jats:italic>R<\/jats:italic>)-ketamine. This study suggest that (<jats:italic>R<\/jats:italic>)-ketamine in the periphery after washout from the brain is metabolized to (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK in the liver, and subsequently, (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK enters into brain tissues. Furthermore, it is unlikely that (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK is essential for the antidepressant actions of (<jats:italic>R<\/jats:italic>)-ketamine in a CSDS model.<\/jats:p>","DOI":"10.1038\/s41598-018-22449-9","type":"journal-article","created":{"date-parts":[[2018,2,27]],"date-time":"2018-02-27T15:10:56Z","timestamp":1519744256000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Lack of metabolism in (R)-ketamine\u2019s antidepressant actions in a chronic social defeat stress model"],"prefix":"10.1038","volume":"8","author":[{"given":"Kai","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,3,5]]},"reference":[{"key":"22449_CR1","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/S0006-3223(99)00230-9","volume":"47","author":"RM Berman","year":"2000","unstructured":"Berman, R. 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