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Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action

The prevailing hypothesis of ketamine’s unique antidepressant effects implicates N-methyl-d-aspartate receptor (NMDAR) inhibition-dependent enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated transmission, activation of intracellular signalling pathways and increase...

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Autores principales: Aleksandrova, Lily R., Wang, Yu Tian, Phillips, Anthony G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292673/
https://www.ncbi.nlm.nih.gov/pubmed/30556028
http://dx.doi.org/10.1177/2470547017743511
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author Aleksandrova, Lily R.
Wang, Yu Tian
Phillips, Anthony G.
author_facet Aleksandrova, Lily R.
Wang, Yu Tian
Phillips, Anthony G.
author_sort Aleksandrova, Lily R.
collection PubMed
description The prevailing hypothesis of ketamine’s unique antidepressant effects implicates N-methyl-d-aspartate receptor (NMDAR) inhibition-dependent enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated transmission, activation of intracellular signalling pathways and increased synaptogenesis. Recently, however, a seminal study by Zanos et al. directly challenged the NMDAR hypothesis of ketamine with the claim that an active ketamine metabolite, (2R,6R)-hydroxynorketamine, devoid of NMDAR binding properties or key side effects of its parent compound, is both necessary and sufficient for ketamine’s antidepressant effects in rodents. However, following these encouraging initial findings, one preclinical study failed to replicate the antidepressant effects of (2R,6R)-hydroxynorketamine (HNK), while others have questioned the metabolite’s contribution to ketamine’s therapeutic effects or argued against rejecting the NMDAR hypothesis of ketamine action. In light of these potentially paradigm-shifting, but highly controversial, findings, this review will summarise and critically evaluate the evidence for and against the NMDA receptor hypothesis of ketamine action, with a particular focus on (2R,6R)-HNK and the implications of its discovery for understanding ketamine’s mechanism of action in depression. Ultimately, uncovering the molecular mechanisms underlying the therapeutic effects of ketamine and possibly (2R,6R)-HNK, will aid the development of novel and more efficacious antidepressant agents so urgently needed to address a major public health concern, and could hold potential for the treatment of other stress-related psychopathologies, including bipolar disorder, post-traumatic stress disorder and suicidality.
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spelling pubmed-62926732018-12-13 Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action Aleksandrova, Lily R. Wang, Yu Tian Phillips, Anthony G. Chronic Stress (Thousand Oaks) Review The prevailing hypothesis of ketamine’s unique antidepressant effects implicates N-methyl-d-aspartate receptor (NMDAR) inhibition-dependent enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated transmission, activation of intracellular signalling pathways and increased synaptogenesis. Recently, however, a seminal study by Zanos et al. directly challenged the NMDAR hypothesis of ketamine with the claim that an active ketamine metabolite, (2R,6R)-hydroxynorketamine, devoid of NMDAR binding properties or key side effects of its parent compound, is both necessary and sufficient for ketamine’s antidepressant effects in rodents. However, following these encouraging initial findings, one preclinical study failed to replicate the antidepressant effects of (2R,6R)-hydroxynorketamine (HNK), while others have questioned the metabolite’s contribution to ketamine’s therapeutic effects or argued against rejecting the NMDAR hypothesis of ketamine action. In light of these potentially paradigm-shifting, but highly controversial, findings, this review will summarise and critically evaluate the evidence for and against the NMDA receptor hypothesis of ketamine action, with a particular focus on (2R,6R)-HNK and the implications of its discovery for understanding ketamine’s mechanism of action in depression. Ultimately, uncovering the molecular mechanisms underlying the therapeutic effects of ketamine and possibly (2R,6R)-HNK, will aid the development of novel and more efficacious antidepressant agents so urgently needed to address a major public health concern, and could hold potential for the treatment of other stress-related psychopathologies, including bipolar disorder, post-traumatic stress disorder and suicidality. SAGE Publications 2017-12-12 /pmc/articles/PMC6292673/ /pubmed/30556028 http://dx.doi.org/10.1177/2470547017743511 Text en © The Author(s) 2017 http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Review
Aleksandrova, Lily R.
Wang, Yu Tian
Phillips, Anthony G.
Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action
title Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action
title_full Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action
title_fullStr Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action
title_full_unstemmed Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action
title_short Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action
title_sort hydroxynorketamine: implications for the nmda receptor hypothesis of ketamine’s antidepressant action
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292673/
https://www.ncbi.nlm.nih.gov/pubmed/30556028
http://dx.doi.org/10.1177/2470547017743511
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