Neuropharmacology最新文献

{"title":"Ligustilide ameliorates cerebral ischemia-reperfusion injury by inhibiting NLRP3 inflammasome-dependent pyroptosis through enhancing Nrf2 signaling","authors":"Yang Wang ,&nbsp;Zhihan Wan ,&nbsp;Ning Wang ,&nbsp;Qian Wu ,&nbsp;Saiwang Seto","doi":"10.1016/j.neuropharm.2025.110642","DOIUrl":"10.1016/j.neuropharm.2025.110642","url":null,"abstract":"<div><div>Pyroptosis is a type of proinflammatory programmed cell death, that closely related to the progress of cerebral ischemia/reperfusion injury (CIRI), and NLRP3 inflammasome is the most classic pathway mediating pyroptosis. Ligustilide (LIG) is a natural compound derived from the traditional Chinese herb chuanxiong hort and angelica sinensis which can penetrate the blood-brain barrier and has a good neuroprotective effect. However, it remains unclear whether LIG could alleviate CIRI by inhibiting pyroptosis. Here, the neuroprotective effect of LIG was verified by reducing NLRP3-mediated pyroptosis, and further exploring whether the inhibition of LIG on pyroptosis was related to Nuclear factor-erythropoietin 2-related factor 2(Nrf2)activation. The results showed that LIG can reduce the injury of brain tissue after ischemia, as well as NLRP3 inflammasome-mediated pyroptosis and neuroinflammation response after MCAO/R in rats. Mechanistically, the effect of LIG on Nrf2 was detected by molecular docking, protein levels and immunofluorescence analysis. We found that LIG promoted the Nrf2 expression and reduced the production of mitochondrial ROS (mtROS), and than inhibited NLRP3 inflammasome-mediated pyroptosis. Particularly revealing was that ML385, the inhibitor of Nrf2, partly blocked the above effects of LIG. All these findings suggest that LIG may ameliorate CIRI through inhibiting NLRP3 inflammasome-mediated pyroptosis dependent on Nrf2 signaling.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110642"},"PeriodicalIF":4.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903761","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":"Abstinence and extinction drive opposing changes in striatal activity and dopamine signaling during alcohol relapse","authors":"Xueyi Xie,&nbsp;Ruifeng Chen,&nbsp;Yufei Huang,&nbsp;Xuehua Wang,&nbsp;Jun Wang","doi":"10.1016/j.neuropharm.2025.110646","DOIUrl":"10.1016/j.neuropharm.2025.110646","url":null,"abstract":"<div><div>Relapse remains a major challenge in the treatment of alcohol use disorder, driven in part by persistent neuroadaptations. However, how different post-alcohol experiences, such as passive withdrawal (abstinence) versus active extinction training, differentially shape the neural circuits and synaptic mechanisms that influence relapse vulnerability remains unclear. Here, we show that these experiences have opposing effects on dorsomedial striatal (DMS) direct-pathway medium spiny neurons (dMSNs) and dopamine dynamics during cue-induced reinstatement of alcohol seeking. Using in vivo fiber photometry in D1-Cre rats, we found that abstinence increased both dopamine release and dMSN calcium activity during reinstatement, whereas extinction training reduced dopamine release and prevented abstinence-related elevation in dMSN activity. Given that dopamine regulates corticostriatal plasticity onto dMSNs, and that such plasticity plays a critical role in alcohol-seeking behavior, these opposing dopamine signals suggest experience-dependent changes in medial prefrontal cortex (mPFC)-to-dMSN synaptic strength that may contribute to relapse vulnerability. To test this, we used pathway-specific optogenetic plasticity protocols and found that inducing long-term depression (LTD) after abstinence attenuated reinstatement, whereas inducing long-term potentiation (LTP) after extinction reinstated alcohol seeking. These findings suggest that dopamine-dependent corticostriatal plasticity bidirectionally mediates relapse and is shaped by prior alcohol-related experience, identifying it as a potential target for relapse prevention.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110646"},"PeriodicalIF":4.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893012","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":"Antidepressant ketamine via oral gavage impairs fear memory, suppresses 22 kHz ultrasonic vocalizations, lowers GluN2A/B expression, and reduces medial habenula activity in rats","authors":"Beenish Asrar,&nbsp;Sude Metin,&nbsp;Zeynep Sen,&nbsp;Gunes Unal","doi":"10.1016/j.neuropharm.2025.110650","DOIUrl":"10.1016/j.neuropharm.2025.110650","url":null,"abstract":"<div><div>Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist known for its rapid-acting antidepressant properties, has been extensively studied through intravenous and intraperitoneal routes. However, despite its growing use in pharmacotherapy, research on oral administration of ketamine remains limited. This study aims to investigate the behavioral and neural effects of fixed-dose oral ketamine delivered via gavage. Adult male Wistar rats were assigned to four groups receiving either saline (vehicle) or ketamine at 15 mg/kg, 30 mg/kg, or 45 mg/kg doses. Animals were tested in the forced swim test (FST), open field test, cued fear conditioning, and elevated plus maze (EPM). Three doses of ketamine were administered via oral gavage every two days, each given 30 min before the FST, fear extinction, and EPM. ELISA was used to measure expression levels of the NMDAR subunit GRIN1 (GluN1), while immunohistochemistry was used for the GluN2A and GluN2B subunits as well as c-Fos. 45 mg/kg ketamine reduced immobility in the FST, transiently impaired fear memory retrieval and reduced ultrasonic vocalizations during Extinction 1. GRIN1 levels were reduced in the hypothalamus for all doses, but increased in the thalamus for higher doses. The antidepressant-like dose decreased the number of GluN2A and GluN2B expressing neurons in the paraventricular nucleus of the thalamus, basolateral amygdala, and habenula. High dose groups also showed diminished c-Fos + cells in the medial habenula following acute stress. These results suggest that 45 mg/kg ketamine via oral gavage produces antidepressant-like effects, through regulation of NMDAR subunits in several depression-related structures like the medial habenula.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110650"},"PeriodicalIF":4.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893013","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 psilocybin administration increases sociability and alters the gut microbiome in male wild-type mice but not in a preclinical model of obsessive-compulsive disorder","authors":"James J. Gattuso ,&nbsp;Geraldine Kong ,&nbsp;Bilgenur Bezcioglu ,&nbsp;Da Lu ,&nbsp;Millicent N. Ekwudo ,&nbsp;Carey Wilson ,&nbsp;Carolina Gubert ,&nbsp;Anthony J. Hannan ,&nbsp;Thibault Renoir","doi":"10.1016/j.neuropharm.2025.110648","DOIUrl":"10.1016/j.neuropharm.2025.110648","url":null,"abstract":"<div><div>Psilocybin, a serotonergic compound that produces psychedelic effects primarily through activation of the 5-HT_2A receptor, has shown promise in treating neuropsychiatric conditions, including obsessive-compulsive disorder (OCD). However, the effects of chronic psilocybin administration on gut function, microbiota, and behavioural phenotypes remain understudied. The present study investigated the effects of chronic psilocybin (0.1 and 1 mg/kg, oral gavage) on gut and behavioural measures in wild-type (WT) and SAPAP3 knockout (KO) mice, a model of OCD-like phenotypes. We present novel evidence that SAPAP3 KO mice exhibit social deficits, and that chronic psilocybin increases sociability in male WT mice. Although no therapeutic effects were observed at either dose on anxiety-, compulsive-, or depressive-like behaviour, chronic psilocybin also did not induce psychosis-like behaviours. A dose-dependent effect of psilocybin was observed on gut motility. Although chronic administration did not significantly alter overall gut microbiome diversity, reductions in <em>Lactobacillus murinus, Lactobacillus animalis</em><em>,</em> and <em>Alistipes dispar</em> were observed in male WT mice, but not in KO mice or female mice. Integrative analysis revealed that a microbial cluster, comprising <em>Lactobacillus</em> and <em>Alistipes</em> species, correlated with locomotion, head-twitch response and gut motility, effectively differentiating psilocybin-treated mice from vehicle controls. This suggests a potential host-microbiome feedback mechanism regulating host serotonin signalling, linked to central and peripheral 5-HT_2A receptor activation. Additionally, separate microbial clusters were associated with startle response and sociability, indicating that psilocybin may engage distinct neural pathways to mediate these behaviours. These findings highlight the importance of considering the microbiome and sex in future psychedelic research and open new avenues for exploring the microbiota-gut-brain axis as a target for future therapeutic strategies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110648"},"PeriodicalIF":4.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903759","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":"TIM3 attenuates morphine antinociceptive tolerance and microglial neuroinflammation by suppressing the TRAF6/NF-κB pathway in male mice","authors":"Huan Yang ,&nbsp;Tong Shen ,&nbsp;Zhi Qi ,&nbsp;Zhong Yang ,&nbsp;Mengyu Zhang ,&nbsp;Jinhong Jiang ,&nbsp;Zhuo Sun ,&nbsp;Chen Lu","doi":"10.1016/j.neuropharm.2025.110638","DOIUrl":"10.1016/j.neuropharm.2025.110638","url":null,"abstract":"<div><div>Chronic morphine administration often leads to the development of antinociceptive tolerance, presenting a significant challenge in the chronic pain management. Although microglia are known to mediate the neuroinflammation associated with morphine-induced antinociceptive tolerance, the molecular mechanisms underlying this process remain incompletely understood. Recent evidence indicates that T cell immunoglobulin domain and mucin domain-3 (TIM3) acts as an important regulator in inflammation-related diseases. In this study, we investigated the role of TIM3 in morphine antinociceptive tolerance. Pharmacological blockade of TIM3 exacerbated morphine antinociceptive tolerance and associated hyperalgesia, whereas upregulation of TIM3 in the spinal cord significantly reduced both the development and maintenance of antinociceptive tolerance. We found that TIM3 negatively regulated microglia-mediated neuroinflammation and neuronal apoptosis following chronic morphine exposure. Mechanistically, TIM3 promoted the degradation of tumor necrosis factor receptor-associated factor 6 (TRAF6) and inhibited the activation of nuclear factor κB (NF-κB) signaling pathways. Furthermore, we identified TRAF6 as a key mediator through which TIM3 attenuated morphine-induced antinociceptive tolerance and suppressed the secretion of proinflammatory factors. Notably, TIM3 interacted with tumor necrosis factor α-induced protein 3 (TNFAIP3) to enhance K48-linked ubiquitination of TRAF6 in morphine-stimulated microglia, thereby mitigating inflammatory responses. Together, these findings suggest that spinal TIM3 negatively modulates morphine antinociceptive tolerance by regulating microglial inflammatory responses through a TNFAIP3/TRAF6/NF-κB-dependent mechanism. This study highlights TIM3 as a promising therapeutic target for preventing morphine antinociceptive tolerance in chronic pain management.</div><div>Schematic diagram for the proposed mechanisms of TIM3 regulates morphine antinociceptive tolerance. TIM3 may alleviate morphine antinociceptive tolerance by suppressing microglia-mediated neuroinflammation and neuronal apoptosis, which is associated with the TRAF6/NF-κB pathway.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110638"},"PeriodicalIF":4.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144885380","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":"Neuropathic pain caused contextual fear generalization by reducing RIN1 expression in dorsal hippocampal CA1 pyramidal neurons","authors":"Qi Zhang,&nbsp;Yu-Bo Gao,&nbsp;Juan Li,&nbsp;Hu-Hu Bai,&nbsp;Xu Yang,&nbsp;Jia-Ning Dang,&nbsp;Xiao-Xue Liu,&nbsp;Xue Bai,&nbsp;Xian Yang,&nbsp;Zhan-Wei Suo,&nbsp;Xiao-Dong Hu","doi":"10.1016/j.neuropharm.2025.110644","DOIUrl":"10.1016/j.neuropharm.2025.110644","url":null,"abstract":"<div><div>Conditioned fear learning enables an organism to use sensory cues to predict potential threats and take adaptive responses to avoid bodily harm. The generalization of fear to safety situations is a common cognitive disorder after traumatic stress. The current study investigated the effect of nerve injury on the fear memory in the mice of both sexes, and found that the neuropathic pain correlated with the contextual fear generalization, a maladaptive fear response to non-threatening environments. Our data showed that Ras and Rab interactor 1 (RIN1), a neuron-specific protein in the brain, was critically involved in the modification of fear memory. Peripheral nerve injury reduced the expression of RIN1 in the dorsal CA1 pyramidal neurons, which led to an enhanced synaptic distribution of N-methyl-D-aspartate (NMDA) subtype glutamate receptors containing GluN2B subunit (GluN2B receptors). Microinjection of GluN2B receptor-selective antagonist ifenprodil into the dorsal CA1 region attenuated the generalized contextual fear without significant influence on the auditory fear memory. Targeted knockdown of RIN1 in the dorsal CA1 pyramidal neurons mimicked the nerve injury by inducing the GluN2B receptor-dependent generalization of contextual fear. These data implicated the contextual fear generalization as one of the anxiety-related disorders during neuropathic pain and indicated an important role of RIN1 in the negative control over the generalized fear.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110644"},"PeriodicalIF":4.6,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144885378","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":"Enteric glia and purinergic signaling in health and disease","authors":"Brian D. Gulbransen ,&nbsp;Alexei Verkhratsky ,&nbsp;Vladimir Parpura","doi":"10.1016/j.neuropharm.2025.110645","DOIUrl":"10.1016/j.neuropharm.2025.110645","url":null,"abstract":"<div><div>We celebrate the life of our colleague Francesco Di Virgilio, who in his very last public lecture discussed purinergic signaling in neuroglia in physiology and pathophysiology. Here, we write on a subset of a unique type of peripheral neuroglia, enteric glia that accompany enteric neurons in the enteric nervous system of the gut and act to maintain homeostasis in enteric neurocircuits. Bi-directional communication between enteric neurons and glia is majorly mediated by purines. Enteric glia also play central roles in regulating the availability of extracellular purines in enteric circuits. Changes in glial purinergic signaling and control mechanisms contribute to neuroplasticity and disease susceptibility in inflammatory contexts. This review summarizes the current state of the field in understanding how enteric glia are involved in purinergic signaling in the enteric nervous system.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110645"},"PeriodicalIF":4.6,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144885379","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":"Exendin-4 protects the dopaminergic neurons by attenuating inflammatory responses of microglial cells via activation of AMPK","authors":"Nikesh Rimal,&nbsp;Shristi Khanal,&nbsp;Ganesh Bohara,&nbsp;Dong-Young Choi","doi":"10.1016/j.neuropharm.2025.110643","DOIUrl":"10.1016/j.neuropharm.2025.110643","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disease characterized by preferential loss of the dopaminergic neurons in the substantia nigra and consequent occurrence of typical symptoms including resting tremor, rigidity and bradykinesia. PD remains a significant challenge due to the lack of disease-modifying drugs despite extensive research efforts. Glucagon-like peptide-1 and its analogues have shown neuroprotective properties. However, its specific molecular mechanisms for the neuroprotection remains to elucidate. In this study, we explored the anti-inflammatory and neuroprotective effects of exendin-4 by employing BV2 microglial cells and the MPTP-induced mouse model for PD. Our study showed that exendin-4 significantly suppressed the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 in LPS-stimulated BV2 cells. Furthermore, exendin-4 increased AMPK phosphorylation and the activation of AMPK by exendin-4 played a crucial role in suppressing the production of proinflammatory cytokines, as addition of compound C, an inhibitor of AMPK diminished the effect. Additionally, exendin-4 demonstrated neuroprotective effects by attenuating SH-SY5Y cell death caused by conditioned media from BV2 cells exposed to LPS. Moreover, exendin-4 attenuated microglial and astroglial activation in the substantia nigra and striatum of MPTP-treated mice, which was accompanied by reduced proinflammatory cytokines. Exendin-4 also improved motor functions of MPTP-treated mice, as determined by beam test and rotarod test. In parallel with the anti-inflammatory effects, exendin-4 attenuated MPTP-mediated dopaminergic neurodegeneration as estimated by immunohistochemistry for tyrosine hydroxylase and HPLC analyses for the striatal dopamine and DOPAC. These results suggest that exendin-4 could be a promising therapeutic agent for PD, offering neuroprotection by modulating inflammatory pathways and preserving dopaminergic neurons.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110643"},"PeriodicalIF":4.6,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863470","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":"Estrogenic regulation of perineuronal nets in the mouse insular cortex and hippocampus","authors":"Rachel Nguyen ,&nbsp;Razia Rahyab ,&nbsp;Ashna Deshpande ,&nbsp;Emily Legge,&nbsp;Jonathas Almeida,&nbsp;Sara M. Herz,&nbsp;Alexia L. Zylko,&nbsp;M. Imad Damaj,&nbsp;Amy W. Lasek","doi":"10.1016/j.neuropharm.2025.110641","DOIUrl":"10.1016/j.neuropharm.2025.110641","url":null,"abstract":"<div><div>Estrogen has profound effects on the brain, affecting neuronal plasticity and behavior. Perineuronal nets (PNNs) are perforated extracellular matrix structures that mostly surround parvalbumin (PV)-expressing inhibitory interneurons and regulate neuronal activity, synaptic plasticity and behavior. PNNs have sex-specific effects on behavior, suggesting that hormones like estrogen may be involved in these sex differences. In this study, we investigated the effects of estrous cycle and estrogen on PNNs in the hippocampus and insular cortex of female mice. PNNs and PV protein were detected by fluorescence labeling with the plant lectin WFA and PV immunostaining, respectively, throughout the estrous cycle, following treatment with estradiol, and after chronic administration of the aromatase inhibitor letrozole to block estrogen synthesis. PNN labeling was highest during estrus and bidirectionally modulated by estradiol levels, with estradiol decreasing, and letrozole increasing, PNN labeling intensity. To interrogate potential mechanisms of estrogenic regulation of PNNs, we used RNAScope to probe the estrogen receptors <em>Esr1</em> and <em>Esr2</em>, and <em>Cyp19a1</em>, encoding aromatase, in PV neurons during estrus and diestrus. In insular PV neurons, <em>Esr2</em> was elevated during estrus, and in hippocampal PV neurons, <em>Cyp19a1</em> was elevated during diestrus. Finally, expression of genes encoding matrix metalloproteinases (MMPs/ADAMTSs) and their endogenous inhibitors (TIMPs) were examined by qPCR following letrozole treatment, with expression changes observed in both the insula and hippocampus. Together, these results indicate that PNN accumulation and degradation in females are regulated by estrogen with distinct region-specific mechanisms contributing to PNN structural changes by estrogen.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110641"},"PeriodicalIF":4.6,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863471","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":"Effects of glucagon-like peptide 1 receptor signaling in the dorsolateral septum on ethanol operant self-administration and relapse behaviors","authors":"Yuqing Xiao,&nbsp;Jo Ann Yap,&nbsp;Zhi Yi Ong","doi":"10.1016/j.neuropharm.2025.110640","DOIUrl":"10.1016/j.neuropharm.2025.110640","url":null,"abstract":"<div><div>Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting more than 400 million people globally. Glucagon-like peptide-1 (GLP-1) has recently shown promise as a treatment for AUD but the underlying neural mechanisms are unclear. Given that dorsolateral septum (dLS) highly expresses GLP-1 receptors and is implicated in reward processing, this study investigated whether GLP-1 reduces ethanol intake and relapse behaviors via dLS. Long Evans rats were given intermittent access to 20 % ethanol solution before receiving training for ethanol operant self-administration. To examine relapse, operant self-administration was extinguished and two relapse tests were conducted: reacquisition of ethanol self-administration and prime + context-induced reinstatement of ethanol seeking. On self-administration test days, rats received intra-dLS injections of GLP-1 receptor agonist Exendin 4 (Ex4; 5 ng, 25 ng) or vehicle. During relapse tests, rats received intra-dLS infusion of either vehicle or 25 ng Ex4. Food intake and body weight were also measured. Results showed that intra-dLS Ex4 (25 ng) reduced ethanol self-administration in male high responders, but not in male low responders or females. Thus, only male rats were included in subsequent relapse tests. Intra-dLS Ex4 also reduced reacquisition of ethanol self-administration but had no impact on prime + context-induced reinstatement. No sustained changes in 24-h food intake or body weight were observed following intra-dLS Ex4 infusions. Finally, retrograde tracing results showed that dLS receive input from NTS GLP-1-expressing neurons. Together, these findings support the dLS as a key region in mediating the effects of GLP-1 receptor signaling on ethanol self-administration and reacquisition but suggest different contributing mechanisms in reinstatement of ethanol seeking.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110640"},"PeriodicalIF":4.6,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862353","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}