Neuropharmacology最新文献

{"title":"Aripiprazole: The antiallodynic and antihyperalgesic effects in chronic constriction injury-induced neuropathic pain and reserpine-induced fibromyalgia with possible mechanisms","authors":"Yagmur Okcay ,&nbsp;Özlem Aykaç ,&nbsp;Rana Arslan ,&nbsp;Nurcan Bektas","doi":"10.1016/j.neuropharm.2025.110454","DOIUrl":"10.1016/j.neuropharm.2025.110454","url":null,"abstract":"<div><div>Neuropathic pain, caused by peripheral or central nerve damage, and fibromyalgia, a chronic musculoskeletal disorder, require complex treatment approaches. This study evaluated the antiallodynic and antihyperalgesic effects of aripiprazole (1, 5, and 10 mg/kg, i. p.) in rats with chronic constriction injury-induced neuropathic pain and reserpine-induced fibromyalgia in female Sprague-Dawley rats, using electronic von Frey and Hargreaves tests. Dopaminergic, serotonergic, and opioidergic systems' roles were assessed through pre-treatment with sulpiride (50 mg/kg), WAY 100635 (1 mg/kg), and naloxone (1 mg/kg), respectively. The effect of aripiprazole was compared with 30 mg/kg pregabalin in the neuropathic pain model and 30 mg/kg duloxetine in the fibromyalgia model. Aripiprazole demonstrated significant antiallodynic and antihyperalgesic activity in both models. It did not change locomotor activity at a dose of 1 mg/kg but caused a decrease at a dose of 5 mg/kg. Dopamine D₂, serotonin 5-HT_1A, and opioidergic receptors contributed to aripiprazole's effects at varying levels. This study highlights the potential use of aripiprazole for managing neuropathic pain and fibromyalgia by targeting multiple receptor systems. The findings demonstrate the potential use of aripiprazole alone or as an adjuvant in the treatments of neuropathic pain and fibromyalgia.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110454"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral and transcriptomic effects of a novel cannabinoid on a rat valproic acid model of autism","authors":"Sally Loomis ,&nbsp;Diogo G. Silva ,&nbsp;Ranjev Savopoulos ,&nbsp;Jackie Cilia ,&nbsp;Jennifer Li ,&nbsp;Mat D. Davis ,&nbsp;David Virley ,&nbsp;Andrew Foley ,&nbsp;Emanuele Loro ,&nbsp;Andrew C. McCreary","doi":"10.1016/j.neuropharm.2025.110450","DOIUrl":"10.1016/j.neuropharm.2025.110450","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social communication, restricted interests, repetitive behavior and irritability. Exposure to valproic acid (VPA) during pregnancy has been shown to increase the risk of autism in children and has led to the development of the <em>in-utero</em> VPA rat model that elicits neurodevelopmental autistic-like features. Offspring exhibit behavioral and neurobiological alterations modelling ASD symptoms. We performed a behavioral and molecular assessment in a rat <em>in-utero</em> VPA model treated with a novel botanical cannabinoid, JZP541.</div><div>Male offspring from dams treated with VPA were tested acutely and sub-chronically with JZP541 (10, 30, or 100 mg/kg, intraperitoneally). A behavioral testing battery was performed, and brain frontal cortex and hippocampus used for RNA sequencing.</div><div>In utero exposure to VPA resulted in progeny showing behavioral phenotypes characteristic of ASD. JZP541 attenuated these deficits in social, stereotypic, hyperactivity and irritability behavior in a dose-dependent fashion.</div><div>VPA exposure was associated with a substantial transcriptional dysregulation impacting multiple key biological processes in a tissue-dependent manner. The expression profiles were integrated with publicly available datasets of autism-associated genes to support the validity of the model used and to focus on the effects of treatment on known autism-relevant transcriptional targets. This approach indicated a strong and dose-dependent reduction of the autism-associated gene expression signature in brain samples from animals dosed with JZP541.</div><div>Our findings demonstrate JZP541 was able to ameliorate ASD associated behavioral deficits, and this was supported by improvements in putative transcriptional biomarkers of ASD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110450"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A putative binding model of nitazene derivatives at the μ-opioid receptor","authors":"Joseph Clayton ,&nbsp;Lei Shi ,&nbsp;Michael J. Robertson ,&nbsp;Georgios Skiniotis ,&nbsp;Michael Michaelides ,&nbsp;Lidiya Stavitskaya ,&nbsp;Jana Shen","doi":"10.1016/j.neuropharm.2025.110437","DOIUrl":"10.1016/j.neuropharm.2025.110437","url":null,"abstract":"<div><div>Nitazenes are a class of novel synthetic opioids with exceptionally high potency. Currently, an experimental structure of <em>μ</em>OR-opioid receptor (<em>μ</em>OR) in complex with a nitazene is lacking. Here we used a suite of computational tools, including consensus docking, conventional molecular dynamics (MD) and metadynamics simulations, to investigate the <em>μ</em>OR binding modes of nitro-containing meto-, eto-, proto-, buto-, and isotonitazenes and nitro-less analogs, metodes-, etodes-, and protodesnitazenes. Docking generated three binding modes, whereby the nitro-substituted or unsubstituted benzimidazole group extends into SP1 (subpocket 1 between transmembrane helix or TM 2 and 3), SP2 (subpocket 2 between TM1, TM2, and TM7) or SP3 (subpocket 3 between TM5 and TM6). Simulations suggest that etonitazene and likely also other nitazenes favor the SP2-binding mode. Comparison to the experimental structures of <em>μ</em>OR in complex with BU72, fentanyl, and mitragynine pseudoindoxyl (MP) allows us to propose a putative model for <em>μ</em>OR-ligand recognition in which ligand can access hydrophobic SP1 or hydrophilic SP2, mediated by the conformational change of Gln124^2.60. Interestingly, in addition to water-mediated hydrogen bonds, the nitro group in nitazenes forms a π-hole interaction with the conserved Tyr75^1.39. Our computational analysis provides new insights into the mechanism of <em>μ</em>OR-opioid recognition, paving the way for investigations of the structure-activity relationships of nitazenes.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110437"},"PeriodicalIF":4.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial damage and ER stress in CB1 receptor antagonist-induced apoptosis in human neuroblastoma SH-SY5Y cells","authors":"Kazuaki Mori ,&nbsp;Akinobu Togo ,&nbsp;Kota Yamashita ,&nbsp;Shigeo Sakuragi ,&nbsp;Hiroko Bannai ,&nbsp;Taishi Umezawa ,&nbsp;Keisuke Ohta ,&nbsp;Toru Asahi ,&nbsp;Chihiro Nozaki ,&nbsp;Kosuke Kataoka","doi":"10.1016/j.neuropharm.2025.110440","DOIUrl":"10.1016/j.neuropharm.2025.110440","url":null,"abstract":"<div><div>Cannabinoid receptor type 1 (CB1R) is the key modulator of neuronal viability. CB1R antagonists provide neuroprotective effects on neurotoxicity caused by e.g. neuronal injury. However, the underlying mechanisms and potential limitations of CB1R antagonism remain unclear. Here we investigated the impact of environmental conditions on CB1R antagonist effects. We have found that cell-permeable CB1R antagonists, rimonabant and AM251, induced cell death in human neuroblastoma SH-SY5Y cells under serum-free conditions. Mitochondrial morphological analysis revealed mitochondrial swelling characterized by their network fragmentation and cristae reduction. Phosphoproteomics analysis showed the ER stress signaling pathway PERK/eIF2α/ATF4/CHOP, leading to caspase-dependent apoptosis. These results suggest that CB1R antagonists promote apoptosis via mitochondrial damage and ER stress under serum-free conditions in SH-SY5Y cells. Our findings indicate that while CB1R antagonists may be neuroprotective in certain conditions, they may also pose a neurotoxic risk in environments characterized by cellular stress or nutrient deprivation.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110440"},"PeriodicalIF":4.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruptions of the oxytocin system impair sociability and cognitive flexibility in a subchronic phencyclidine model of schizophrenia","authors":"Coleman Sapp ,&nbsp;Megan Rich ,&nbsp;Karla Hess ,&nbsp;Allison Losco ,&nbsp;Abigail Zupancic ,&nbsp;Heather K. Caldwell","doi":"10.1016/j.neuropharm.2025.110442","DOIUrl":"10.1016/j.neuropharm.2025.110442","url":null,"abstract":"<div><div>Previous research suggests that the oxytocin (Oxt) system may play a role in the etiology of schizophrenia. To investigate, we used a subchronic phencyclidine (PCP) mouse model to test how disruption of Oxt or the Oxt receptor (Oxtr) affects schizophrenia-related behaviors. Specifically, we assessed how subchronic PCP impacted hyperlocomotion, sociability, and passive stress coping in male Oxt and Oxtr knockout (−/−) and wildtype (+/+) mice. Additionally, we evaluated immediate early gene activation in Oxtr −/− and +/+ mice to identify brain regions where the Oxt system might impact schizophrenia-associated behaviors. Lastly, we investigated cognitive flexibility in Oxtr −/− and +/+ mice. We found that subchronic PCP treatment decreased social interactions in Oxt −/− mice as compared to Oxt +/+ mice, with no genotypic differences in the Oxtr line of mice. Increased c-Fos expression was observed in Oxtr −/− mice relative to Oxtr +/+ controls in the medial amygdala and the paraventricular nucleus of the hypothalamus following a forced swim test. Finally, we found deficits in cognitive flexibility in Oxtr −/− mice treated with PCP, relative to Oxtr +/+ mice. These findings are consistent with the hypothesis that Oxt may buffer against some of the schizophrenia-associated symptoms induced by subchronic PCP treatment. Based on the data, we speculate that compensatory mechanisms may be able to accommodate the loss of the Oxt system, depending on the origin of the dysfunction and the behavioral endpoint in question. These findings also add support to data linking disruption of Oxt system signaling to schizophrenia.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110442"},"PeriodicalIF":4.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronopharmacokinetics of the antidepressant paroxetine: An in vitro and in vivo approach","authors":"Soraia Silva ,&nbsp;Joana Bicker ,&nbsp;Amílcar Falcão ,&nbsp;Robert Dallmann ,&nbsp;Ana Fortuna","doi":"10.1016/j.neuropharm.2025.110441","DOIUrl":"10.1016/j.neuropharm.2025.110441","url":null,"abstract":"<div><div>The circadian rhythm influences homeostatic functions such as sleep, physical activity and food intake as well as pharmacotherapy, namely pharmacokinetics.</div><div>To investigate the impact of the circadian rhythm on the pharmacokinetics of paroxetine, <em>in vitro</em> synchronized permeability studies were carried out in a tri-culture blood-brain barrier model. Paroxetine demonstrated lower apparent permeability when the cells were incubated at 24 h post-synchronization than at 36 h. Additionally, <em>in vivo</em> chronopharmacokinetic studies were performed in CD-1 female mice administered with paroxetine (5 mg/kg) by intranasal route in the early morning or evening. Paroxetine exposure in the brain was higher when it was administered at the beginning of the active phase (ZT13) compared with the rest phase (ZT1) (p &lt; 0.001), probably owing to the lower levels of P-glycoprotein expressed in the brain at the active phase (p &lt; 0.05). Since melatonin production depends on serotonin, its plasma concentrations were also assessed <em>in vivo.</em> The results demonstrated that melatonin concentrations increased 12 h after paroxetine nasal instillation at ZT13 (p &lt; 0.05), but remained unchanged at ZT1, suggesting that the drug effect is influenced by administration time.</div><div>In conclusion, the circadian rhythm impacted the pharmacokinetics of paroxetine, especially its distribution into the brain, the target organ. This emphasizes the importance of the time of administration in antidepressant dosing, highlighting its relevance for future studies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110441"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting mitochondria-regulated ferroptosis: A new frontier in Parkinson's disease therapy","authors":"Wenjun Wang ,&nbsp;Elizabeth Rosalind Thomas ,&nbsp;Ruyue Xiao ,&nbsp;Tianshun Chen ,&nbsp;Qulian Guo ,&nbsp;Kezhi Liu ,&nbsp;You Yang ,&nbsp;Xiang Li","doi":"10.1016/j.neuropharm.2025.110439","DOIUrl":"10.1016/j.neuropharm.2025.110439","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantial nigra. Mitochondrial dysfunction and mitochondrial oxidative stress are central to the pathogenesis of PD, with recent evidence highlighting the role of ferroptosis - a type of regulated cell death dependent on iron metabolism and lipid peroxidation. Mitochondria, the central organelles for cellular energy metabolism, play a pivotal role in PD pathogenesis through the production of Reactive oxygen species (ROS) and the disruption of iron homeostasis. This review explores the intricate interplay between mitochondrial dysfunction and ferroptosis in PD, focusing on key processes such as impaired electron transport chain function, tricarboxylic acid (TCA) cycle dysregulation, disruption of iron metabolism, and altered lipid peroxidation. We discuss key pathways, including the role of glutathione (GSH), mitochondrial ferritin, and the regulation of the mitochondrial labile iron pool (mLIP), which collectively influence the susceptibility of neurons to ferroptosis. Furthermore, this review emphasizes the importance of mitochondrial quality control mechanisms, such as mitophagy and mitochondrial biogenesis, in mitigating ferroptosis-induced neuronal death. Understanding these mechanisms linking the interplay between mitochondrial dysfunction and ferroptosis may pave the way for novel therapeutic approaches aimed at preserving mitochondrial integrity and preventing neuronal loss in PD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110439"},"PeriodicalIF":4.6,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acid amide hydrolase in comorbid borderline personality disorder and major depressive disorder: Imaging with [11C]CURB PET","authors":"Michelle A. De Pol ,&nbsp;Dorsa Rafiei ,&nbsp;Jeffrey H. Meyer ,&nbsp;Kimberly L. Desmond ,&nbsp;Shelley McMain ,&nbsp;Isabelle Boileau ,&nbsp;Jerry Warsh ,&nbsp;Pablo Rusjan ,&nbsp;Christian Schmahl ,&nbsp;Neil Vasdev ,&nbsp;Lauren R. Gray ,&nbsp;Ryan Aloysius ,&nbsp;Nathan J. Kolla","doi":"10.1016/j.neuropharm.2025.110436","DOIUrl":"10.1016/j.neuropharm.2025.110436","url":null,"abstract":"<div><div>Borderline personality disorder (BPD) is highly comorbid with major depressive disorder (MDD), and the comorbid condition is associated with poorer treatment outcomes, which necessitates the investigation of transdiagnostic biomarkers. Previous research suggests that fatty acid amide hydrolase (FAAH), an endocannabinoid enzyme, is elevated in the prefrontal cortex (PFC) in BPD; however, no study has examined FAAH density in individuals with comorbid conditions. We hypothesized that FAAH level would be elevated in the prefrontal cortex, anterior cingulate cortex and hippocampus of comorbid BPD + MDD compared to healthy controls, as these brain regions are linked to the pathobiology of both disorders. For an exploratory analysis, we hypothesized that brain FAAH would be positively correlated with symptom severity, aggression, and impulsivity. Fifteen unmedicated BPD + MDD cases and 15 age- and sex-matched healthy controls underwent a [¹¹C]CURB positron emission tomography scan to measure λk₃, an index of available FAAH. No significant group differences in [¹¹C]CURB λk₃ were observed between BPD + MDD patients and controls. Negative correlations were found between [¹¹C]CURB λk₃ and physical aggression scores in the dorsolateral PFC (r = −0.64, p = 0.04), ventrolateral PFC (r = −0.75, p = 0.01), medial PFC (r = −0.64, p = 0.03), and orbitofrontal cortex (r = −0.66, p = 0.03) in the BPD + MDD group. A positive correlation was found between [¹¹C]CURB λk₃ and impulsivity, as measured by the Barratt Impulsiveness Scale-11, in the ventrolateral PFC (r = 0.62, p = 0.04) of the BPD + MDD group. We suggest that the negative correlations between [¹¹C]CURB λk₃ and physical aggression could reflect a relationship between FAAH and planned aggression whereas the latter findings may reflect a positive relationship with impulsivity.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110436"},"PeriodicalIF":4.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic nicotine enhances object recognition memory via inducing long-term potentiation in the medial prefrontal cortex in mice","authors":"Shoma Izumi,&nbsp;Ibuki Kawasaki,&nbsp;Fuka Waki,&nbsp;Keisuke Nishikawa,&nbsp;Naoya Nishitani,&nbsp;Satoshi Deyama,&nbsp;Katsuyuki Kaneda","doi":"10.1016/j.neuropharm.2025.110435","DOIUrl":"10.1016/j.neuropharm.2025.110435","url":null,"abstract":"<div><div>Chronic nicotine administration enhances cognitive functions, including learning and memory, and ameliorates cognitive impairments observed in psychological and neurodegenerative disorders. However, the detailed mechanisms underlying these effects are not fully understood. In this study, we used a novel object recognition (NOR) test and <em>in vitro</em> slice electrophysiology in mice to investigate the involvement of the medial prefrontal cortex (mPFC), a brain region connected to the hippocampus, and the synaptic plasticity within this region in chronic nicotine-induced object recognition memory enhancement. The NOR test revealed that chronic nicotine administration for five consecutive days significantly enhanced object recognition memory in male and female mice. This effect was blocked by intra-mPFC infusion of mecamylamine (Mec), a non-selective nicotinic acetylcholine receptor (nAChR) antagonist. In parallel with these findings, whole-cell recordings demonstrated that chronic nicotine administration significantly increased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/<em>N</em>-methyl-<span>d</span>-aspartate (NMDA) ratio in mPFC layer V pyramidal neurons in male but not female mice. This plastic change was suppressed by systemic injection of Mec or methyllycaconitine, an α7 nAChR antagonist. Furthermore, optogenetic erasure of long-term potentiation (LTP) through chromophore-assisted light inactivation of cofilin, a protein essential for stabilizing spine expansion, suppressed chronic nicotine-induced enhancement of recognition memory. These findings suggest that chronic nicotine administration induces LTP in mPFC pyramidal neurons, likely enhancing object recognition memory.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110435"},"PeriodicalIF":4.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute stress enhances synaptic plasticity in male mice via a microbiota-dependent mechanism","authors":"Cristina Rosell-Cardona ,&nbsp;Michael K. Collins ,&nbsp;Kenneth J. O'Riordan ,&nbsp;Michael S. Goodson ,&nbsp;Nancy Kelley-Loughnane ,&nbsp;John F. Cryan ,&nbsp;Gerard Clarke","doi":"10.1016/j.neuropharm.2025.110434","DOIUrl":"10.1016/j.neuropharm.2025.110434","url":null,"abstract":"<div><div>Acute stress can enhance or impair synaptic plasticity depending on the nature, duration, and type of stress exposure as well as the brain region examined. The absence of a gut microbiome can also alter hippocampal plasticity. However, the possible interplay between synaptic plasticity, acute stress, and the gut microbiota remains unknown. Here, we examine this interaction and determine whether the gut microbiota impacts stress-induced alterations in hippocampal plasticity. Further, we explored whether exposure to the microbial metabolite butyrate is sufficient to counteract stress-induced alterations in synaptic plasticity. We used electrophysiological and molecular experiments in adult male C57/BL6 antibiotic-treated and acutely stressed mice.</div><div>In electrophysiological experiments we treated hippocampal slices with 3 μM sodium butyrate to explore the effect of this microbial metabolite. We found the presence of the microbiota essential for the enhancement of both short- and long-term potentiation induced by 15 min of acute restraint stress. Furthermore, butyrate exposure effectively restored the stress-induced enhancement of potentiation in slices from microbiome-depleted animals while also enhancing long-term potentiation independent of stress. In addition, alterations of hippocampal synaptic plasticity markers were noted.</div><div>Our findings highlight a critical new temporal role for gut-derived metabolites in defining the impact of acute stress on synaptic plasticity.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110434"},"PeriodicalIF":4.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}