Neuropharmacology最新文献

{"title":"Corrigendum to “Enriched environment mitigates cognitive impairment in pre-adolescent mice following repeated neonatal sevoflurane exposure by reducing TTBK1 expression and Tau phosphorylation” [Neuropharmacology 268 (2025) 110327]","authors":"Yang Yu , Jiafeng Yu , Banglin Wu , Yuanlin Wang , Yun Li , Yongyan Yang , Yonghao Yu , Jingyu Feng","doi":"10.1016/j.neuropharm.2025.110388","DOIUrl":"10.1016/j.neuropharm.2025.110388","url":null,"abstract":"","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110388"},"PeriodicalIF":4.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537455","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}

{"title":"Pro-inflammatory mediators sensitise transient receptor potential melastatin 3 cation channel (TRPM3) function in mouse sensory neurons","authors":"Javier Aguilera-Lizarraga,&nbsp;Tony K. Lim,&nbsp;Luke A. Pattison,&nbsp;Luke W. Paine,&nbsp;David C. Bulmer,&nbsp;Ewan St John Smith","doi":"10.1016/j.neuropharm.2025.110391","DOIUrl":"10.1016/j.neuropharm.2025.110391","url":null,"abstract":"<div><div>Pro-inflammatory mediators can directly activate pain-sensing neurons, known as nociceptors. Additionally, these mediators can sensitise ion channels and receptors expressed by these cells through transcriptional and post-translational modulation, leading to nociceptor hypersensitivity. A well-characterised group of ion channels that subserve nociceptor sensitisation is the transient receptor potential (TRP) superfamily of cation channels. For example, the roles of TRP channels vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in nociceptor sensitisation and inflammatory pain have been extensively documented. In the case of TRP melastatin 3 (TRPM3), however, despite the increasing recognition of this channel's role in inflammatory pain, the mediators driving its sensitisation during inflammation remain poorly characterised. Here, using Ca²⁺ imaging, we found that an inflammatory soup of bradykinin, interleukin 1β (IL-1β) and tumour necrosis factor α (TNFα) sensitised TRPM3 function in isolated mouse sensory neurons; IL-1β and TNFα, but not bradykinin, independently potentiated TRPM3 function. TRPM3 expression and translocation to the membrane remained unchanged upon individual or combined exposure to these inflammatory mediators, which suggests that post-translational modification might occur. Finally, using the complete Freund's adjuvant-induced model of knee inflammation, we found that systemic pharmacological blockade of TRPM3 does not alleviate inflammatory pain (as assessed through evaluation of digging behaviour and dynamic weight bearing), which contrasts with previous reports using different pain models. We propose that the nuances of the immune response may determine the relative contribution of TRPM3 to nociceptive signalling in different neuro-immune contexts. Collectively, our findings improve insight into the role of TRPM3 sensitisation in inflammatory pain.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110391"},"PeriodicalIF":4.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528660","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}

{"title":"Maternal N-acetylcysteine supplementation in lactation ameliorates metabolic and cognitive deficits in adult offspring exposed to maternal obesity","authors":"Eden Yonatan ,&nbsp;Orya Noa Shukha ,&nbsp;Idit Golani ,&nbsp;Saher Abu-ata ,&nbsp;Yaseen Awad-Igbaria ,&nbsp;Nizar Khatib ,&nbsp;Yuval Ginsberg ,&nbsp;Eilam Palzur ,&nbsp;Ron Beloosesky ,&nbsp;Alon Shamir","doi":"10.1016/j.neuropharm.2025.110390","DOIUrl":"10.1016/j.neuropharm.2025.110390","url":null,"abstract":"<div><div>Maternal obesity in pregnancy and lactation is linked to metabolic disturbances and neurodevelopmental problems in offspring, increasing the risk of psychiatric disorders in adulthood. We proposed that maternal N-acetyl cysteine (NAC) supplementation during lactation, a critical period for neurodevelopment, potentially protects offspring from developing cognitive impairment in adulthood. Fifteen young female ICR mice were randomly allocated to different experimental groups: high-fat diet (HFD; 60.3% fat before mating, during pregnancy and lactation), HFD-NAC of 300 mg/kg/day during lactation, CD (high-fat diet before mating, during pregnancy, and regular chow control diet of 8.2% fat during lactation), CD-NAC of 300 mg/kg/day during lactation and control group consuming regular chow diet. The serum inflammatory markers of the offspring were evaluated post-weaning, while metabolic markers, microglial density, and cognitive performance were assessed in adulthood using the novel Object Recognition and Morris Water Maze tests. Our results demonstrate maternal obesity during gestation and lactation increased body weight, hepatic steatosis, and microglial cell density in the dentate gyrus (DG) and cortex. Furthermore, these offspring exhibited reduced spatial learning abilities in adulthood, regardless of sex. However, maternal NAC administration during lactation and maternal diet intervention significantly reduced brain microglial density and improved both male and female offspring metabolic profiles. More importantly, NAC supplementation during lactation, regardless of maternal diet, enhanced male offspring's learning ability in adulthood. Our findings indicate that administering NAC to obese mothers during the critical lactation period may offer protection against metabolic disturbances and cognitive deficits in adult offspring previously exposed to maternal obesity.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110390"},"PeriodicalIF":4.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537464","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}

{"title":"β-2 agonist and antagonist adrenoceptors induce neuroprotection in a progressive model of parkinsonism","authors":"Auderlan M. de Gois ,&nbsp;José M.M. Bispo ,&nbsp;Edson R. Santos ,&nbsp;Marina F. Souza ,&nbsp;João E.C. Melo ,&nbsp;Mylaine S. Mendonça ,&nbsp;Thiago H. Almeida-Souza ,&nbsp;Enilton A. Camargo ,&nbsp;Katty A.A.L. Medeiros ,&nbsp;Pollyana C. Leal ,&nbsp;Heitor F. Santos ,&nbsp;Lívia C.R.F. Lins ,&nbsp;Alessandra M. Ribeiro ,&nbsp;Regina H. Silva ,&nbsp;José R. Santos","doi":"10.1016/j.neuropharm.2025.110386","DOIUrl":"10.1016/j.neuropharm.2025.110386","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive dopaminergic dysfunction in the nigrostriatal pathway, as well as alterations in other monoamines systems. Research indicates that the use of β-adrenergic agonist and antagonists influences the risk of PD. This study evaluated the effects of salbutamol and propranolol on motor and neurochemical parameters in a progressive model of parkinsonism induced by reserpine (RES). Male Wistar rats were chronically treated with 12 subcutaneous injections of RES (0,1 mg/kg) given every other day for 24 days. From the 16th day onwards, the animals were daily treated with salbutamol (5 mg/kg) or propranolol (20 mg/kg) intraperitoneally for 8 days. Salbutamol reduced the motor deficit caused by RES in the catalepsy test, while propranolol reduced the damages caused by RES in the vacuous chewing movements evaluation. In immunohistochemical analysis both salbutamol and propranolol prevented dopaminergic damage in the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), striatum and noradrenergic damage in locus coeruleus (LC). In addition, salbutamol and propranolol prevented the increase in α-synuclein immunoreactivity caused by RES in the substantia nigra pars reticulata (SNr), striatum, prefrontal cortex (mPFC) and hippocampus. These data show that salbutamol and propranolol promote neuroprotective effects against reserpine-induced parkinsonism. However, further studies are needed to understand the mechanisms involved in β-adrenoceptors role in PD development.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110386"},"PeriodicalIF":4.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537466","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":"Oxytocin enhances acquisition in a social trust task in mice, whereas both oxytocin and its antagonist block trust violation learning","authors":"Samuel Budniok ,&nbsp;Zsuzsanna Callaerts-Vegh ,&nbsp;Marian Bakermans-Kranenburg ,&nbsp;Guy Bosmans ,&nbsp;Rudi D'Hooge","doi":"10.1016/j.neuropharm.2025.110389","DOIUrl":"10.1016/j.neuropharm.2025.110389","url":null,"abstract":"<div><div>The complex effects of the neurohormone oxytocin (OT) on socio-cognitive phenomena have recently been proposed to be complementary with safety learning, where a stimulus acquires safety-predicting properties when it predicts non-occurrence of an aversive event. OT may enhance salience of safety stimuli and promote positive social behavior, such as trust, by reducing anxiety and stress. Complementary, OT may reduce the ability to modulate previously learned behaviors based on new, contradicting information. This occurs through its attenuation of prediction error (PE)—the discrepancy between expectations and actual outcomes. In the current study, we modulated OT receptor (OTR) activity by administering an agonist (OT) and antagonist (cligosiban, CL), and subjected male and female mice to our social transmission of food preference (STFP) protocol to assess social safety learning. STFP is based on the observation that food neophobia of rodents is attenuated when a conspecific signals the safety of the food. We used safe food preference as putative murine homologue of human trust acquisition<em>,</em> and modeled trust violation (PE) using lithium chloride (LiCl)-induced food aversion after social interaction. In males, results revealed that OT enhanced trust acquisition, whereas both OT and its antagonist CL similarly blocked trust violation learning. None of the manipulations affected female behavior. Our findings highlight the complexities of OT's role in social behavior, emphasizing caution in therapeutic manipulations of this system.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110389"},"PeriodicalIF":4.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531001","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":"Omega-3-Enriched Fish oil reduces the chemotherapy-induced peripheral neuropathy in mice","authors":"Jessica Melato ,&nbsp;Fernanda Capitanio Goldoni ,&nbsp;Larissa Benvenutti ,&nbsp;Thiago Patrício Corrêa ,&nbsp;Aline Pertile Remor ,&nbsp;Karina Giacomini Varela ,&nbsp;Luis Carlos Stoeberl ,&nbsp;Gabriel Gripp Fernandes ,&nbsp;Giulia de Lima Rasga ,&nbsp;Giselle Fazzioni Passos ,&nbsp;Miriam Anders Apel ,&nbsp;Luiz Carlos Klein-Junior ,&nbsp;José Roberto Santin ,&nbsp;Robson da Costa ,&nbsp;Nara Lins Meira Quintão","doi":"10.1016/j.neuropharm.2025.110384","DOIUrl":"10.1016/j.neuropharm.2025.110384","url":null,"abstract":"<div><div>Cancer is a leading cause of mortality and morbidity worldwide and conventional chemotherapy frequently induce irreversible adverse effects in patients. Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of both paclitaxel (PTX) and oxaliplatin (OXA) chemotherapies, affecting approximately 30–50% of patients. As cancer survival rates have improved, the efforts of scientific community to develop new strategies for preventing CIPN are also growing. This study presents the effects of omega-3 (ω-3)-enriched fish oil supplementation on the hypersensitivity induced by PTX or OXA in mice. GC-MS analysis of the fish oil revealed an amount of EPA and DHA corresponding to 55.2% and 37.4% of total oil composition, respectively. The thirty-day supplementation with the fish oil prevented the cold hypersensitivity induced by the acute OXA injection protocol, with reduction of spinal cord microglia activation, as well as decreased levels of cytokines and BDNF in the spinal cord and brain. A similar effect was observed with the chronic OXA administration, reducing both mechanical and thermal hypersensitivity. The fish oil also prevented PTX-induced neuropathy, accompanied by a reduction in cytokine levels. It is important to mention that biochemical parameters such as total cholesterol, triglycerides and glucose were also normalised. The fish oil supplementation prevented the development of hypersensitivity in both OXA and PTX models, with reduced neuroinflammation likely being the main mechanism behind this effect. The fish oil supplementation, either before or during chemotherapy, could be an important ally to prevent and treat CIPN, improving the patients’ quality of life post-cancer treatment.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110384"},"PeriodicalIF":4.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520651","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":"Vortioxetine attenuates rotenone-induced enteric neuroinflammation via modulation of the TLR2/S100B/RAGE signaling pathway in a rat model of Parkinson's disease","authors":"Dilara Nemutlu Samur ,&nbsp;Sendegül Yıldırım ,&nbsp;Erkan Maytalman ,&nbsp;Merzuka Kalay ,&nbsp;Gamze Tanrıöver ,&nbsp;Gül Özbey","doi":"10.1016/j.neuropharm.2025.110385","DOIUrl":"10.1016/j.neuropharm.2025.110385","url":null,"abstract":"<div><div>Emerging evidence suggests that gastrointestinal dysfunction and enteric nervous system pathology play a critical role in the early stages of Parkinson's disease. Considering the bidirectional relationship between gastrointestinal symptoms and mood disorders, this study aimed to elucidate the effects and possible mechanisms of action of vortioxetine, a serotonergic antidepressant, on the pathophysiological changes induced by rotenone in the enteroglial cells. α-synuclein, phosphorylated α-synuclein, TLR2, S100B and RAGE expression were detected in duodenal tissues of rats administered rotenone (2 mg/kg/day, s.c.) and/or vortioxetine (10 mg/kg/day, s.c.) for 28 days. For the mechanism of action studies, rat-derived enteroglial cells were treated with rotenone (10 μM) and/or vortioxetine (5 μM or 1 μM) for 24 h. The effects of vortioxetine were evaluated in the presence of the TLR2 antagonist C29, RAGE antagonist FPS-ZM1 and the S100B inhibitor pentamidine. TLR2, S100B, RAGE, and NFκB mRNA levels and proinflammatory cytokines via RT-qPCR and ELISA. Our results demonstrate that rotenone treatment significantly increased α-synuclein, pS129-α-synuclein, TLR2, and S100B expression while reducing RAGE levels, indicating marked enteric pathology. Vortioxetine administration attenuated these effects, reducing α-synuclein accumulation and proinflammatory markers. <em>In vitro</em>, rotenone impaired glial responses, decreasing S100B, RAGE, and NFκB markers, while vortioxetine improved these responses, promoting resynthesis of inflammatory molecules. Notably, S100B, NFκB, and cytokine levels (TNF-α, IL-1β, IL-6) were affected by C29, FPS-ZM1, and pentamidine pretreatments. Thus, vortioxetine is thought to have beneficial effects on rotenone-induced pathological changes in EGCs, and some of these effects are thought to be mediated by the TLR2/S100B/RAGE pathway.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110385"},"PeriodicalIF":4.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143509267","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":"Red nucleus mGluR4 and mGluR8 inhibit nociception and the development of neuropathic pain by restraining the expressions of TNF-α and IL-1β","authors":"Ya-Li Xu ,&nbsp;Yu-Tong Xia ,&nbsp;Miao-Miao Zhang ,&nbsp;Yue-Jia Li ,&nbsp;Xiao-Xia Tao ,&nbsp;Ke Li ,&nbsp;Qing-Qing Yang ,&nbsp;Xue Tian ,&nbsp;Ji-Bo Wu ,&nbsp;Ya-Ting Shi ,&nbsp;Jun-Yang Wang ,&nbsp;Xiao-Yan Zeng","doi":"10.1016/j.neuropharm.2025.110387","DOIUrl":"10.1016/j.neuropharm.2025.110387","url":null,"abstract":"<div><div>Metabotropic glutamate receptors (mGluR) participate in pain modulation and mediate different effects in nociceptive stimuli, relying on the receptor subtype activated and its anatomical location. Here, we addressed the functions of mGluR Ⅲ group (mGluR4, mGluR6, mGluR7, and mGluR8) in the red nucleus (RN) in nociception and the development of neuropathic pain induced by spared nerve injury (SNI) using male rats. Our results showed that mGluR4, mGluR7, and mGluR8, except for mGluR6, were constitutively expressed in the RN of normal rats. At 2 weeks post-SNI, the expressions of mGluR4 and mGluR8 rather than mGluR7 were reduced in the RN contralateral to the nerve lesion. Unilateral administration of mGluR Ⅲ antagonist MSOP to the RN of normal rats decreased the PWT of contralateral hindpaw and evoked pronounced mechanical allodynia, which was blocked by mGluR4 agonist VU0155041 or mGluR8 agonist AZ12216052 instead of mGluR7 agonist AMN082. Moreover, administration of VU0155041 or AZ12216052 to the RN contralateral to the nerve injury at 2 weeks post-SNI alleviated SNI-induced neuropathic pain. Further studies indicated that administration of MSOP to the RN of normal rats increased the expressions of nociceptive factors TNF-α and IL-1β, which were blocked by VU0155041 or AZ12216052 instead of AMN082. Additionally, administration of VU0155041 or AZ12216052 to the RN at 2 weeks post-SNI inhibited the overexpressions of TNF-α and IL-1β induced by SNI. These findings suggest that red nucleus mGluR4 and mGluR8 instead of mGluR7 inhibit nociception and the development of neuropathic pain by restraining the expressions of TNF-α and IL-1β.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110387"},"PeriodicalIF":4.6,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143509266","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}

{"title":"Microglial phagocytosis and regulatory mechanisms: Key players in the pathophysiology of depression","authors":"Man Wang ,&nbsp;Guimin Jin ,&nbsp;Tingting Duan ,&nbsp;Run Li ,&nbsp;Yubin Gao ,&nbsp;Ming Yu ,&nbsp;Yuhao Xu","doi":"10.1016/j.neuropharm.2025.110383","DOIUrl":"10.1016/j.neuropharm.2025.110383","url":null,"abstract":"<div><div>Depression is a globally prevalent emotional disorder with a complex pathophysiology. Microglia are resident immune cells in the central nervous system, playing crucial roles in regulating inflammation, synaptic plasticity, immune phagocytosis, and other functions, thereby exerting significant impacts on neuropsychiatric disorders like depression. Increasing research indicates that abnormal phagocytic function of microglia in the brain is involved in depression, showing excessive or insufficient phagocytosis in different states. Here, we have provided a review of the signaling molecules involved in microglial phagocytosis in depression, including “eat me” signals such as phosphatidylserine (PS), complement, and “don't eat me” signals such as CD47, CD200 and related receptors. Furthermore, we discuss the regulatory effects of existing pharmaceuticals and dietary nutrients on microglial phagocytosis in depression, emphasizing the need for tailored modulation based on the varying phagocytic states of microglia. This review aims to facilitate a deeper understanding of the role of microglial phagocytosis in depression and provide a roadmap for potential therapeutic strategies for depression targeting microglial phagocytosis.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110383"},"PeriodicalIF":4.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493036","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":"Hippocampus muscarinic M4 receptor mRNA expression may influence central cholinergic activity, causing fear memory strengthening by peripheral adrenaline","authors":"Ana Oliveira ,&nbsp;Márcia Azevedo ,&nbsp;Rafaela Seixas ,&nbsp;Soraia Silva ,&nbsp;Raquel Martinho ,&nbsp;Paula Serrão ,&nbsp;Elisabete Silva ,&nbsp;Mónica Moreira-Rodrigues","doi":"10.1016/j.neuropharm.2025.110382","DOIUrl":"10.1016/j.neuropharm.2025.110382","url":null,"abstract":"<div><div>Adrenaline (Ad) strengthens contextual fear memory by increasing blood glucose, possibly enhancing hippocampus acetylcholine synthesis. Nevertheless, it is unclear if peripheral Ad influences the cholinergic system, contributing to contextual fear memory strengthening. We aimed to evaluate whether peripheral Ad alters muscarinic receptor expression and if the cholinergic system is involved in peripheral Ad contextual fear memory strengthening effect.</div><div>Wild-type (WT) and Ad-deficient male mice (129 × 1/SvJ) underwent a fear conditioning procedure followed by intraperitoneal pre-training and pre-context administration of Ad (0.1 mg/kg), atropine (10 mg/kg), methylatropine (0.5 mg/kg), Ad (0.1 mg/kg) plus atropine (10 mg/kg) or vehicle (NaCl, 0.9%). Shock responsiveness and freezing behaviour were accessed. Hippocampal M₁, M₂, and M₄ mRNA expression were evaluated.</div><div>Ad-deficient mice presented decreased hippocampal muscarinic M₄ subtype receptor mRNA expression compared to WT mice. In Ad-administered Ad-deficient mice, hippocampal muscarinic M₄ subtype receptor mRNA expression increased compared with vehicle-administered Ad-deficient mice. On the context day, atropine-administered WT mice presented decreased freezing behaviour compared to vehicle or methylatropine-administered WT mice. Moreover, Ad plus atropine-administered Ad-deficient mice led to decreased freezing behaviour compared to Ad-administered Ad-deficient mice.</div><div>In conclusion, Ad-deficient mice's contextual fear memory impairment was associated with hippocampal muscarinic M₄ subtype receptor down expression, which was reversed by Ad. This may be related to contextual fear memory consolidation or retrieval induced by peripheral Ad. Furthermore, the effect of Ad contextual fear memory might be due to increased hippocampus muscarinic subtype M₄ expression, which may contribute to increased cholinergic activity in the central nervous system.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110382"},"PeriodicalIF":4.6,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483723","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}