title: What is hydroxynorketamine and what can it bring to neurotherapeutics?
abstract: (R,S)-Ketamine was initially developed as an anesthetic agent and its pharmacological properties were determined on the basis of this clinical use. However, pharmacological studies in rat led to the development of the 'Ketamine Paradigm', whereby (R,S)-ketamine and its N-demethylated metabolite (R,S)-norketamine were deemed the active compounds whereas the other ketamine metabolites were considered inactive. Recent in vivo and in vitro studies with (2S,6S)-hydroxynorketamine, a previously identified 'inactive' metabolite, have demonstrated that this compound is an active and selective inhibitor of the α7 subtype of the nicotinic acetylcholine receptor and that this activity contributes to the pharmacological responses associated with the antidepressant activity of (R,S)-ketamine. Thus, it appears that it is necessary to reassess the 'Ketamine Paradigm' in regards to the use of sub-anesthetic doses of (R,S)-ketamine in the treatment of treatment-resistant depression.
authors.affiliation: Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD , USA.
authors.forename: Nagendra S
authors.initials: NS
authors.lastname: Singh
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Michel
authors.initials: M
authors.lastname: Bernier
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy*; D006801:Humans; D007649:Ketamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine; C033419:norketamine
keywords: D-serine; NMDA receptor; depression; nicotinic acetylcholine receptors; serine racemase