(R,S)-ketamine and (2R,6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

Abstract A single subanesthetic infusion of ketamine can rapidly alleviate symptoms of treatment-resistant major depression. Since repeated administration is required to sustain symptom remission, it is important to characterize the potential untoward effects of prolonged ketamine exposure. While st...

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Autores principales:	Lace M. Riggs, Xiaoxian An, Edna F. R. Pereira, Todd D. Gould
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/3c665b6efe044095b2dd0e68c18d5190
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spelling	oai:doaj.org-article:3c665b6efe044095b2dd0e68c18d51902021-11-14T12:11:19Z(R,S)-ketamine and (2R,6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency10.1038/s41398-021-01685-02158-3188https://doaj.org/article/3c665b6efe044095b2dd0e68c18d51902021-11-01T00:00:00Zhttps://doi.org/10.1038/s41398-021-01685-0https://doaj.org/toc/2158-3188Abstract A single subanesthetic infusion of ketamine can rapidly alleviate symptoms of treatment-resistant major depression. Since repeated administration is required to sustain symptom remission, it is important to characterize the potential untoward effects of prolonged ketamine exposure. While studies suggest that ketamine can alter cognitive function, it is unclear to what extent these effects are modulated by the frequency or chronicity of treatment. To test this, male and female adolescent (postnatal day [PD] 35) and adult (PD 60) BALB/c mice were treated for four consecutive weeks, either daily or thrice-weekly, with (R,S)-ketamine (30 mg/kg, intraperitoneal) or its biologically active metabolite, (2R,6R)-hydroxynorketamine (HNK; 30 mg/kg, intraperitoneal). Following drug cessation, memory performance was assessed in three operationally distinct tasks: (1) novel object recognition to assess explicit memory, (2) Y-maze to assess working memory, and (3) passive avoidance to assess implicit memory. While drug exposure did not influence working memory performance, thrice-weekly ketamine and daily (2R,6R)-HNK led to explicit memory impairment in novel object recognition independent of sex or age of exposure. Daily (2R,6R)-HNK impaired implicit memory in the passive-avoidance task whereas thrice-weekly (2R,6R)-HNK tended to improve it. These differential effects on explicit and implicit memory possibly reflect the unique mechanisms by which ketamine and (2R,6R)-HNK alter the functional integrity of neural circuits that subserve these distinct cognitive domains, a topic of clinical and mechanistic relevance to their antidepressant actions. Our findings also provide additional support for the importance of dosing frequency in establishing the cognitive effects of repeated ketamine exposure.Lace M. RiggsXiaoxian AnEdna F. R. PereiraTodd D. GouldNature Publishing GrouparticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENTranslational Psychiatry, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Lace M. Riggs Xiaoxian An Edna F. R. Pereira Todd D. Gould (R,S)-ketamine and (2R,6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency
description	Abstract A single subanesthetic infusion of ketamine can rapidly alleviate symptoms of treatment-resistant major depression. Since repeated administration is required to sustain symptom remission, it is important to characterize the potential untoward effects of prolonged ketamine exposure. While studies suggest that ketamine can alter cognitive function, it is unclear to what extent these effects are modulated by the frequency or chronicity of treatment. To test this, male and female adolescent (postnatal day [PD] 35) and adult (PD 60) BALB/c mice were treated for four consecutive weeks, either daily or thrice-weekly, with (R,S)-ketamine (30 mg/kg, intraperitoneal) or its biologically active metabolite, (2R,6R)-hydroxynorketamine (HNK; 30 mg/kg, intraperitoneal). Following drug cessation, memory performance was assessed in three operationally distinct tasks: (1) novel object recognition to assess explicit memory, (2) Y-maze to assess working memory, and (3) passive avoidance to assess implicit memory. While drug exposure did not influence working memory performance, thrice-weekly ketamine and daily (2R,6R)-HNK led to explicit memory impairment in novel object recognition independent of sex or age of exposure. Daily (2R,6R)-HNK impaired implicit memory in the passive-avoidance task whereas thrice-weekly (2R,6R)-HNK tended to improve it. These differential effects on explicit and implicit memory possibly reflect the unique mechanisms by which ketamine and (2R,6R)-HNK alter the functional integrity of neural circuits that subserve these distinct cognitive domains, a topic of clinical and mechanistic relevance to their antidepressant actions. Our findings also provide additional support for the importance of dosing frequency in establishing the cognitive effects of repeated ketamine exposure.
format	article
author	Lace M. Riggs Xiaoxian An Edna F. R. Pereira Todd D. Gould
author_facet	Lace M. Riggs Xiaoxian An Edna F. R. Pereira Todd D. Gould
author_sort	Lace M. Riggs
title	(R,S)-ketamine and (2R,6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency
title_short	(R,S)-ketamine and (2R,6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency
title_full	(R,S)-ketamine and (2R,6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency
title_fullStr	(R,S)-ketamine and (2R,6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency
title_full_unstemmed	(R,S)-ketamine and (2R,6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency
title_sort	(r,s)-ketamine and (2r,6 r)-hydroxynorketamine differentially affect memory as a function of dosing frequency
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/3c665b6efe044095b2dd0e68c18d5190
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(R,S)-ketamine and (2R,6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

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