Agnieszka Pałucha-Poniewiera, Bartosz Bobula, Anna Rafało-Ulińska, Katarzyna Kaczorowska
{"title":"慢性不可预测的轻度应激引起的小鼠抑郁样效应可通过mGlu5受体的部分负变构调节剂M-5MPEP迅速逆转。","authors":"Agnieszka Pałucha-Poniewiera, Bartosz Bobula, Anna Rafało-Ulińska, Katarzyna Kaczorowska","doi":"10.1007/s00213-024-06724-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>Due to the numerous limitations of ketamine as a rapid-acting antidepressant drug (RAAD), research is still being conducted to find an effective and safe alternative to this drug. Recent studies indicate that the partial mGlu<sub>5</sub> receptor negative allosteric modulator (NAM), 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), has therapeutic potential as an antidepressant.</p><p><strong>Objectives: </strong>The study aimed to investigate the potential rapid antidepressant-like effect of M-5MPEP in a mouse model of depression and to determine the mechanism of this action.</p><p><strong>Methods: </strong>Chronic unpredictable mild stress (CUMS) was used as an animal model of depression. The effects of single and four-day administration of M-5MPEP on CUMS-induced animal behaviors reflecting anhedonia, apathy, and helplessness were studied. Western blot was applied to measure the levels of proteins potentially involved in a rapid antidepressant effect, including mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), tropomyosin receptor kinase B (TrkB), and serotonin transporter (SERT), both in the hippocampus and the prefrontal cortex (PFC). Furthermore, excitatory synaptic transmission and long-term potentiation (LTP) were measured in the medial PFC (mPFC).</p><p><strong>Results: </strong>We showed that M-5MPEP administration for four consecutive days abolished CUMS-induced apathy- and anhedonia-like symptoms in a mouse model of depression. We also found that these effects were accompanied by changes in hippocampal TrkB levels and mTOR and eEF2 levels in the PFC. Using electrophysiological techniques, we showed that the four-day M-5MPEP treatment reversed chronic stress-induced increases in excitatory synaptic potential and CUMS-impaired LTP in the mPFC.</p><p><strong>Conclusions: </strong>Partial mGlu<sub>5</sub> receptor NAM, M-5MPEP, appears to be a potentially effective new RAAD and deserves further study.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Depression-like effects induced by chronic unpredictable mild stress in mice are rapidly reversed by a partial negative allosteric modulator of mGlu<sub>5</sub> receptor, M-5MPEP.\",\"authors\":\"Agnieszka Pałucha-Poniewiera, Bartosz Bobula, Anna Rafało-Ulińska, Katarzyna Kaczorowska\",\"doi\":\"10.1007/s00213-024-06724-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Rationale: </strong>Due to the numerous limitations of ketamine as a rapid-acting antidepressant drug (RAAD), research is still being conducted to find an effective and safe alternative to this drug. Recent studies indicate that the partial mGlu<sub>5</sub> receptor negative allosteric modulator (NAM), 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), has therapeutic potential as an antidepressant.</p><p><strong>Objectives: </strong>The study aimed to investigate the potential rapid antidepressant-like effect of M-5MPEP in a mouse model of depression and to determine the mechanism of this action.</p><p><strong>Methods: </strong>Chronic unpredictable mild stress (CUMS) was used as an animal model of depression. The effects of single and four-day administration of M-5MPEP on CUMS-induced animal behaviors reflecting anhedonia, apathy, and helplessness were studied. Western blot was applied to measure the levels of proteins potentially involved in a rapid antidepressant effect, including mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), tropomyosin receptor kinase B (TrkB), and serotonin transporter (SERT), both in the hippocampus and the prefrontal cortex (PFC). Furthermore, excitatory synaptic transmission and long-term potentiation (LTP) were measured in the medial PFC (mPFC).</p><p><strong>Results: </strong>We showed that M-5MPEP administration for four consecutive days abolished CUMS-induced apathy- and anhedonia-like symptoms in a mouse model of depression. We also found that these effects were accompanied by changes in hippocampal TrkB levels and mTOR and eEF2 levels in the PFC. Using electrophysiological techniques, we showed that the four-day M-5MPEP treatment reversed chronic stress-induced increases in excitatory synaptic potential and CUMS-impaired LTP in the mPFC.</p><p><strong>Conclusions: </strong>Partial mGlu<sub>5</sub> receptor NAM, M-5MPEP, appears to be a potentially effective new RAAD and deserves further study.</p>\",\"PeriodicalId\":20783,\"journal\":{\"name\":\"Psychopharmacology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-11-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Psychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00213-024-06724-4\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00213-024-06724-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Depression-like effects induced by chronic unpredictable mild stress in mice are rapidly reversed by a partial negative allosteric modulator of mGlu5 receptor, M-5MPEP.
Rationale: Due to the numerous limitations of ketamine as a rapid-acting antidepressant drug (RAAD), research is still being conducted to find an effective and safe alternative to this drug. Recent studies indicate that the partial mGlu5 receptor negative allosteric modulator (NAM), 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), has therapeutic potential as an antidepressant.
Objectives: The study aimed to investigate the potential rapid antidepressant-like effect of M-5MPEP in a mouse model of depression and to determine the mechanism of this action.
Methods: Chronic unpredictable mild stress (CUMS) was used as an animal model of depression. The effects of single and four-day administration of M-5MPEP on CUMS-induced animal behaviors reflecting anhedonia, apathy, and helplessness were studied. Western blot was applied to measure the levels of proteins potentially involved in a rapid antidepressant effect, including mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), tropomyosin receptor kinase B (TrkB), and serotonin transporter (SERT), both in the hippocampus and the prefrontal cortex (PFC). Furthermore, excitatory synaptic transmission and long-term potentiation (LTP) were measured in the medial PFC (mPFC).
Results: We showed that M-5MPEP administration for four consecutive days abolished CUMS-induced apathy- and anhedonia-like symptoms in a mouse model of depression. We also found that these effects were accompanied by changes in hippocampal TrkB levels and mTOR and eEF2 levels in the PFC. Using electrophysiological techniques, we showed that the four-day M-5MPEP treatment reversed chronic stress-induced increases in excitatory synaptic potential and CUMS-impaired LTP in the mPFC.
Conclusions: Partial mGlu5 receptor NAM, M-5MPEP, appears to be a potentially effective new RAAD and deserves further study.
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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