Agnieszka Pałucha-Poniewiera, Anna Rafało-Ulińska, Agata Faron-Górecka, Paulina Pabian, Katarzyna Kaczorowska
{"title":"(R)-氯胺酮在小鼠慢性不可预测轻度应激抑郁症模型中诱导mGlu5受体依赖的抗抑郁样作用。","authors":"Agnieszka Pałucha-Poniewiera, Anna Rafało-Ulińska, Agata Faron-Górecka, Paulina Pabian, Katarzyna Kaczorowska","doi":"10.1007/s00213-025-06803-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>(S)-Ketamine, which is used to treat depression, has significant undesirable effects and has potential for abuse. A safe alternative to (S)-ketamine is (R)-ketamine. The relationship between (R)-ketamine and the mGlu<sub>5</sub> receptor is unknown, although screening tests indicate the possibility of potentiation of the antidepressant effect of (R)-ketamine by the mGlu<sub>5</sub> receptor negative allosteric modulator (NAM).</p><p><strong>Objectives: </strong>We aimed to investigate whether the antidepressant-like effect of (R)-ketamine is mGlu<sub>5</sub> receptor-dependent. Specifically, we investigated the possibility of enhancing (R)-ketamine antidepressant-like effects using the partial mGlu<sub>5</sub> receptor NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), in a chronic unpredictable mild stress (CUMS) model of depression in mice.</p><p><strong>Methods: </strong>The effect of (R)-ketamine on mGlu<sub>5</sub> receptor availability in the mouse brain was investigated using an autoradiographic method. Animal behaviors reflecting anhedonia, apathy, and helplessness were analyzed to study the rapid and sustained antidepressant-like effects of the combined administration of (R)-ketamine and M-5MPEP. Hippocampal protein levels were measured via Western blotting.</p><p><strong>Results: </strong>(R)-Ketamine altered mGlu<sub>5</sub> receptor availability in several mouse brain regions. Importantly, in the hippocampus, (R)-ketamine reversed CUMS-induced effects. Behavioral studies revealed that M-5MPEP enhanced the effectiveness of a subeffective dose of (R)-ketamine. This drug combination effectively reduced CUMS-induced apathy- and anhedonia-like behavior symptoms. Changes in hippocampal eukaryotic elongation factor2 (eEF2) and tropomyosin receptor kinase B (TrkB) levels accompanied these effects.</p><p><strong>Conclusions: </strong>The weakening of mGlu<sub>5</sub> receptor function in the hippocampus appears to be related to the (R)-ketamine antidepressant-like effect, and coadministration of the partial mGlu<sub>5</sub> receptor NAM, M-5MPEP, might increase its antidepressant activity.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"(R)-ketamine induces mGlu<sub>5</sub> receptor-dependent antidepressant-like effects in the chronic unpredictable mild stress model of depression in mice.\",\"authors\":\"Agnieszka Pałucha-Poniewiera, Anna Rafało-Ulińska, Agata Faron-Górecka, Paulina Pabian, Katarzyna Kaczorowska\",\"doi\":\"10.1007/s00213-025-06803-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Rationale: </strong>(S)-Ketamine, which is used to treat depression, has significant undesirable effects and has potential for abuse. A safe alternative to (S)-ketamine is (R)-ketamine. The relationship between (R)-ketamine and the mGlu<sub>5</sub> receptor is unknown, although screening tests indicate the possibility of potentiation of the antidepressant effect of (R)-ketamine by the mGlu<sub>5</sub> receptor negative allosteric modulator (NAM).</p><p><strong>Objectives: </strong>We aimed to investigate whether the antidepressant-like effect of (R)-ketamine is mGlu<sub>5</sub> receptor-dependent. Specifically, we investigated the possibility of enhancing (R)-ketamine antidepressant-like effects using the partial mGlu<sub>5</sub> receptor NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), in a chronic unpredictable mild stress (CUMS) model of depression in mice.</p><p><strong>Methods: </strong>The effect of (R)-ketamine on mGlu<sub>5</sub> receptor availability in the mouse brain was investigated using an autoradiographic method. Animal behaviors reflecting anhedonia, apathy, and helplessness were analyzed to study the rapid and sustained antidepressant-like effects of the combined administration of (R)-ketamine and M-5MPEP. Hippocampal protein levels were measured via Western blotting.</p><p><strong>Results: </strong>(R)-Ketamine altered mGlu<sub>5</sub> receptor availability in several mouse brain regions. Importantly, in the hippocampus, (R)-ketamine reversed CUMS-induced effects. Behavioral studies revealed that M-5MPEP enhanced the effectiveness of a subeffective dose of (R)-ketamine. This drug combination effectively reduced CUMS-induced apathy- and anhedonia-like behavior symptoms. 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(R)-ketamine induces mGlu5 receptor-dependent antidepressant-like effects in the chronic unpredictable mild stress model of depression in mice.
Rationale: (S)-Ketamine, which is used to treat depression, has significant undesirable effects and has potential for abuse. A safe alternative to (S)-ketamine is (R)-ketamine. The relationship between (R)-ketamine and the mGlu5 receptor is unknown, although screening tests indicate the possibility of potentiation of the antidepressant effect of (R)-ketamine by the mGlu5 receptor negative allosteric modulator (NAM).
Objectives: We aimed to investigate whether the antidepressant-like effect of (R)-ketamine is mGlu5 receptor-dependent. Specifically, we investigated the possibility of enhancing (R)-ketamine antidepressant-like effects using the partial mGlu5 receptor NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), in a chronic unpredictable mild stress (CUMS) model of depression in mice.
Methods: The effect of (R)-ketamine on mGlu5 receptor availability in the mouse brain was investigated using an autoradiographic method. Animal behaviors reflecting anhedonia, apathy, and helplessness were analyzed to study the rapid and sustained antidepressant-like effects of the combined administration of (R)-ketamine and M-5MPEP. Hippocampal protein levels were measured via Western blotting.
Results: (R)-Ketamine altered mGlu5 receptor availability in several mouse brain regions. Importantly, in the hippocampus, (R)-ketamine reversed CUMS-induced effects. Behavioral studies revealed that M-5MPEP enhanced the effectiveness of a subeffective dose of (R)-ketamine. This drug combination effectively reduced CUMS-induced apathy- and anhedonia-like behavior symptoms. Changes in hippocampal eukaryotic elongation factor2 (eEF2) and tropomyosin receptor kinase B (TrkB) levels accompanied these effects.
Conclusions: The weakening of mGlu5 receptor function in the hippocampus appears to be related to the (R)-ketamine antidepressant-like effect, and coadministration of the partial mGlu5 receptor NAM, M-5MPEP, might increase its antidepressant activity.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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