(R)-Ketamine Induces a Greater Increase in Prefrontal 5-HT Release Than (S)-Ketamine and Ketamine Metabolites via an AMPA Receptor-Independent Mechanism.

Animals Disease Models, Animal Dopamine / metabolism Dose-Response Relationship, Drug Ketamine / administration & dosage Lipopolysaccharides Male Mice Microdialysis Microinjections Norepinephrine / metabolism Prefrontal Cortex / metabolism Quinoxalines / pharmacology Receptors, AMPA / metabolism Serotonin / metabolism Stereoisomerism
(R)-ketamine (S)-ketamine AMPA receptors monoamine prefrontal cortex

Journal

The international journal of neuropsychopharmacology
ISSN: 1469-5111
Titre abrégé: Int J Neuropsychopharmacol
Pays: England
ID NLM: 9815893

Informations de publication

Date de publication:
01 10 2019
Historique:
received: 13 06 2019
revised: 02 07 2019
accepted: 16 07 2019
pubmed: 22 7 2019
medline: 20 5 2020
entrez: 21 7 2019
Statut: ppublish

Résumé

Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine's action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice. The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis. (R)-Ketamine and (S)-ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in serotonin and noradrenaline but not dopamine release. (S)-NK increased dopamine and noradrenaline but not serotonin release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), attenuated (S)-ketamine-induced, but not (R)-ketamine-induced serotonin release, whereas NBQX blocked dopamine release induced by both enantiomers. Local application of (R)-ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of (S)-ketamine. (R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.

Sections du résumé

BACKGROUND
Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine's action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice.
METHODS
The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis.
RESULTS
(R)-Ketamine and (S)-ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in serotonin and noradrenaline but not dopamine release. (S)-NK increased dopamine and noradrenaline but not serotonin release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), attenuated (S)-ketamine-induced, but not (R)-ketamine-induced serotonin release, whereas NBQX blocked dopamine release induced by both enantiomers. Local application of (R)-ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of (S)-ketamine.
CONCLUSIONS
(R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.

Identifiants

DOI: 10.1093/ijnp/pyz041 PMID: 31325908 PMC: PMC6822138
pubmed: 31325908
pii: 5536638
doi: 10.1093/ijnp/pyz041
pmc: PMC6822138
doi:

Substances chimiques

Lipopolysaccharides 0
Quinoxalines 0
Receptors, AMPA 0
2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline 118876-58-7
Serotonin 333DO1RDJY
Ketamine 690G0D6V8H
Dopamine VTD58H1Z2X
Norepinephrine X4W3ENH1CV

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

665-674

Informations de copyright

© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.

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Auteurs

Yukio Ago (Y)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Wataru Tanabe (W)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Momoko Higuchi (M)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Shinji Tsukada (S)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Tatsunori Tanaka (T)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Takumi Yamaguchi (T)

Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Hisato Igarashi (H)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Rei Yokoyama (R)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Kaoru Seiriki (K)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Interdisciplinary Program for Biomedical Sciences, Institute for Transdisciplinary Graduate Degree Programs, Osaka University, Suita, Osaka, Japan.

Atsushi Kasai (A)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Takanobu Nakazawa (T)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

Shinsaku Nakagawa (S)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Kenji Hashimoto (K)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Hitoshi Hashimoto (H)

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka, Japan.
Division of Bioscience, Institute for Datability Science, Osaka University, Suita, Osaka, Japan.
Transdimensional Life Imaging Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan.

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Classifications MeSH

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Recherchemedicale.com › Techniques d'investigation › Techniques de chimie analytique › Microdialyse › (R)-Ketamine Induces a Greater Increase in...
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Recherchemedicale.com › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Cortex cérébral › Lobe frontal › Cortex préfrontal › (R)-Ketamine Induces a Greater Increase in...
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Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs au glutamate › Récepteurs ionotropes du glutamate › Récepteur de l'AMPA › (R)-Ketamine Induces a Greater Increase in...
Recherchemedicale.com › Facteurs biologiques › Médiateurs de l'inflammation › Autacoïdes › Sérotonine › (R)-Ketamine Induces a Greater Increase in...
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