Neuropharmacology最新文献

{"title":"Teneurin-4 knockdown disrupts dopamine dynamics and attenuates methamphetamine-induced behaviors","authors":"Wenbing Chen ,&nbsp;Jun Yokose ,&nbsp;Naotaka Izuo ,&nbsp;Yusuke Yano ,&nbsp;Tomoya Kaigawa ,&nbsp;Nobuyuki Kai ,&nbsp;Chikako Kamiyoshihara ,&nbsp;Noriaki Ohkawa ,&nbsp;Yuki Shigetsura ,&nbsp;Shin-ichi Muramatsu ,&nbsp;Atsumi Nitta","doi":"10.1016/j.neuropharm.2025.110817","DOIUrl":"10.1016/j.neuropharm.2025.110817","url":null,"abstract":"<div><div>Methamphetamine (METH) addiction is a major global public health issue with significant societal consequences. Dopamine (DA) plays a central role in the neurobiological mechanisms of METH addiction, particularly by reinforcing reward pathways and modulating neuronal plasticity. Teneurin-4 (TENM4), a type II transmembrane protein, is essential for neural development and for establishing precise synaptic connectivity. However, the specific role of TENM4 in the nucleus accumbens (NAc) during METH-induced reward remains unclear. Here, we found that repeated METH exposure selectively increased TENM4 protein expression in the nucleus accumbens (NAc), prompting us to investigate its function using an AAV-CRISPR-mediated knockdown (TENM4KD) targeted to the NAc in mice. TENM4KD significantly attenuated the development of METH-induced conditioned place preference, without altering METH-induced hyperlocomotion. This behavioral deficit was paralleled by blunted dopamine dynamics; fiber photometry revealed impaired predictive DA signals during conditioning, and microdialysis confirmed a reduction in both basal and METH-evoked DA levels. Mechanistically, this impairment was not due to damage to dopaminergic neurons themselves but was linked to a loss of local GABAergic neurons within the medial NAc and a compensatory upregulation of the dopamine transporter (DAT). These findings uncover a critical role for TENM4 in maintaining the integrity of local NAc circuits that govern reward learning. Thus, TENM4 emerges as a potential molecular target for therapeutic intervention, as manipulating its expression in the NAc disrupts local inhibitory signaling and reduces METH-induced addictive behaviors.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110817"},"PeriodicalIF":4.6,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834377","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":"Age-dependent transcriptomic effects of morphine in the frontal cortex of female mice","authors":"Jarvis Savage ,&nbsp;Anupama Rai ,&nbsp;Jonathan D. Lee ,&nbsp;Jane Banahan ,&nbsp;Kristina Dujic ,&nbsp;Masiel Nunez ,&nbsp;Barbara Caldarone ,&nbsp;Sarbani Ghoshal ,&nbsp;Frank J. Slack ,&nbsp;Maria Mavrikaki","doi":"10.1016/j.neuropharm.2025.110809","DOIUrl":"10.1016/j.neuropharm.2025.110809","url":null,"abstract":"<div><div>Increasing lifespans make health problems in the elderly such as opioid misuse a more prominent concern. Understanding the effects that opioids may have on the aged brain can help us address age-related concerns of opioid exposure. This study aimed to assess potential interactions between aging and opioid exposure. Three-month-old (young adult) and 19-month-old (aged) C57BL/6JN mice were assigned to either a morphine (3 mg/kg, i.p.) or saline group. A conditioned placed preference (CPP) task was used to assess reward sensitivity, while rotarod and beam walk tests were used to assess sensorimotor coordination. To assess for potential age-dependent effects of morphine on gene expression, we performed RNA sequencing in the prefrontal cortex (PFC). We found that morphine induced CPP in both age groups. Our results indicate impaired motor coordination in aged mice; however, morphine did not significantly affect motor coordination in either age group, although a trend toward an increased number of slips was observed in morphine-treated aged mice. Transcriptomic analysis revealed more robust effects of morphine on gene expression in the aged brain compared to the young brain. Interestingly, we found limited overlap between morphine-regulated genes in young and old mice, suggesting that the molecular effects of morphine are age-dependent. Taken together, while we found no significant interactions between morphine (at the tested dose) and aging in the behavioral assays, morphine caused age-dependent gene expression changes. Our findings suggest that age should be considered when prescribing opioids and that age-specific therapeutics may help address opioid use disorder in the elderly.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110809"},"PeriodicalIF":4.6,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781538","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 treatment-resistant social anxiety with sitagliptin: Effects on social fear and comorbid depressive-like behavior in a preclinical model","authors":"Iulia Zoicas,&nbsp;Johannes Kornhuber","doi":"10.1016/j.neuropharm.2025.110812","DOIUrl":"10.1016/j.neuropharm.2025.110812","url":null,"abstract":"<div><div>Social anxiety disorder (SAD) is often complicated by comorbid depression and resistance to standard treatments, yet therapeutic strategies that effectively address both core and comorbid symptoms remain limited. We previously demonstrated that sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor commonly used in the treatment of type 2 diabetes mellitus, effectively reduces social fear in mice subjected to social fear conditioning (SFC), an ethologically valid model of SAD. In the present study, we extend these findings by evaluating the efficacy of sitagliptin in reducing social fear and preventing the development of comorbid depressive-like behavior in acid sphingomyelinase-deficient (ASM−/−) mice, a genetically defined model of antidepressant-resistant emotional behavior. Chronic oral administration of sitagliptin (100 mg/kg/day) significantly reduced social fear in both male and female ASM+/+ and ASM−/− mice following SFC. Notably, sitagliptin also prevented the emergence of depressive-like behavior in both genotypes, as well as the increase in anxiety-like behavior observed specifically in ASM−/− mice, two hallmark comorbidities in the SFC model. These findings indicate that sitagliptin exerts dual-action effects on both primary and comorbid behavioral symptoms of SAD, including in individuals resistant to conventional antidepressant treatment. Given its established clinical use and safety profile, sitagliptin may represent a promising candidate for repurposing as an early intervention in complex, treatment-resistant forms of SAD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110812"},"PeriodicalIF":4.6,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834383","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":"Cftr nominates a novel therapeutic target for Alzheimer's disease: Evidence from integrative omics and in vitro validation","authors":"Hao-Ran Li ,&nbsp;Jun-Zhuo Shi ,&nbsp;Meng-Jie Zhang ,&nbsp;Lu-Yao Yun ,&nbsp;Yun-Feng Zhou ,&nbsp;Yang-Yang He ,&nbsp;Xi Li ,&nbsp;Guan-Hua Du ,&nbsp;Xiao-Bin Pang ,&nbsp;Meng-Wei Wang ,&nbsp;Xin-Mei Xie ,&nbsp;Jie-Jian Kou","doi":"10.1016/j.neuropharm.2025.110808","DOIUrl":"10.1016/j.neuropharm.2025.110808","url":null,"abstract":"<div><div>Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This study applied an integrated transcriptomics and untargeted metabolomics approach to hippocampal tissues from wild-type and 3 × Tg-AD mice to identify AD-associated molecular alterations and key pathways. KEGG pathway enrichment analysis of significantly differentially expressed genes and metabolites identified several core candidate genes, including <em>C5ar1</em>, <em>Gabrg1</em>, <em>Ptger1</em>, <em>Tac1</em>, <em>Lpar2</em>, <em>Pnp2</em>, <em>Cftr</em>, and <em>Sstr3</em>. PCR-based validation in both <em>in vivo</em> and <em>in vitro</em> models confirmed Cftr as the most promising candidate for further investigation. In Aβ₂₅-₃₅-induced cellular AD models, Cftr knockdown or pharmacological inhibition activated the NLRP3 inflammasome pathway, exacerbating neuroinflammation and oxidative stress, whereas enhancing Cftr activity attenuated these pathological processes. These results establish Cftr as a potential therapeutic target for AD and reveal that its modulation of NLRP3 inflammasome signaling represents a strategic avenue for mitigating neuroinflammation and oxidative stress, suggesting a promising direction for intervening in AD progression.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110808"},"PeriodicalIF":4.6,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768687","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":"Cell models to probe the biological bases of antipsychotic-induced metabolic Syndrome: towards an individual specific approach","authors":"Maria Fiore ,&nbsp;Silvia Saltarelli ,&nbsp;Laura De Mastro ,&nbsp;Enrico D'Ambrosio ,&nbsp;Antonia Ianniello ,&nbsp;Alessandro Bertolino ,&nbsp;Giulio Pergola ,&nbsp;Maria Favia ,&nbsp;Antonio Rampino","doi":"10.1016/j.neuropharm.2025.110814","DOIUrl":"10.1016/j.neuropharm.2025.110814","url":null,"abstract":"<div><h3>Background</h3><div>Individuals with major psychiatric disorders are at an increased risk of developing Metabolic Syndrome (MetS), partly attributed to the dysmetabolic side effects of Second-Generation Antipsychotics (SGAs). <em>In vitro</em> cell models of peripheral tissues provide a valid platform to investigate the biochemical and molecular alterations induced by SGAs at the peripheral level in conjunction with their effects on the central nervous system. This scoping review summarizes two decades of studies utilizing established cell lines and primary rodent cells to examine the direct dysmetabolic effects of antipsychotics (APs) on lipid and glucose metabolism, inflammatory pathways, and mitochondrial function.</div></div><div><h3>Methods</h3><div>We identified published scientific literature in the PubMed database using the following search strategy: (“antipsychotic” OR “olanzapine” OR “clozapine” OR “risperidone” OR “quetiapine” OR “haloperidol”) AND (“metabolic syndrome” OR “insulin action” OR “insulin resistance” OR “up-regulation” OR “down-regulation” OR “dyslipidemia”) AND (cell models).</div></div><div><h3>Results</h3><div>Out of 121 articles identified, 21 met the eligibility criteria and were included in the review, with their methods and findings organized according to the AP-affected biological processes implicated in MetS.</div></div><div><h3>Conclusions</h3><div>Independent studies on cell models confirm the AP-pathogenic role on gene and protein expression regulation involved in lipid and glucose metabolism, inflammatory processes, and impairments at the mitochondrial level.</div><div>In the final section of the manuscript, we highlight the potential of individual-specific stem-cell–based models, like induced pluripotent stem cells, to investigate gene-by-medication interactions relevant to AP-induced MetS. However, these stem-cell approaches fall outside the scope of the present review and were not included in our literature search.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110814"},"PeriodicalIF":4.6,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841835","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":"Osthole ameliorates cognitive impairment in ovariectomized rats via estrogen-mediated enhancement of cholinergic function and regulation of neurotransmitter homeostasis","authors":"Yanman Liu ,&nbsp;Jimei Zhang ,&nbsp;Wenjuan Li ,&nbsp;Qingwen Qu ,&nbsp;Zhengxing Shan ,&nbsp;Chunwei Liu ,&nbsp;Ke Jiao ,&nbsp;Xueqin Hou","doi":"10.1016/j.neuropharm.2025.110806","DOIUrl":"10.1016/j.neuropharm.2025.110806","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&amp;E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen–cholinergic–NGF axis: E₂, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110806"},"PeriodicalIF":4.6,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757148","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":"HCN channel inhibitor ZD7288 in the lateral septum attenuates methamphetamine-induced behavior sensitization and relapse","authors":"Shishi Lai ,&nbsp;Wenpei Zhang ,&nbsp;Cailing Wang ,&nbsp;Ying Xu ,&nbsp;Shaolei Jiang ,&nbsp;Xiaofei Deng ,&nbsp;Mei Zhu ,&nbsp;Gaowei Chen ,&nbsp;Kuikui Zhou ,&nbsp;Yingjie Zhu ,&nbsp;Kunhua Wang","doi":"10.1016/j.neuropharm.2025.110811","DOIUrl":"10.1016/j.neuropharm.2025.110811","url":null,"abstract":"<div><div>Drug addiction involves dysregulation in limbic circuits, with the lateral septum (LS) playing a critical role in regulating drug reward and behavioral sensitization. Although chronic methamphetamine (METH) upregulates hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the LS, the therapeutic potential of targeting these channels remains unclear. Here, using pharmacological approaches in mice, we demonstrate that the HCN channel inhibitor ZD7288—administered either locally into the LS or systemically—attenuates METH-induced memory retrieval, the development and expression of locomotor sensitization, without impairing memory acquisition. Furthermore, ZD7288 reduced both METH self-administration acquisition and cue-induced reinstatement. These effects were associated with the normalization of METH-induced neuronal hyperexcitability in the LS. Importantly, ZD7288 did not affect natural reward processing, such as food consumption and social interaction. Our results identify LS HCN channels as potential therapeutic targets for METH use disorder.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110811"},"PeriodicalIF":4.6,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794287","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":"Evaluating tocilizumab in ischemic stroke: Findings from the SPAN multicenter trial","authors":"Anjali Chauhan ,&nbsp;Eunyoung Angela Lee ,&nbsp;Rakesh B. Patel ,&nbsp;Mariia Kumskova ,&nbsp;Enrique C. Leira ,&nbsp;Anil K. Chauhan ,&nbsp;Yanrong Shi ,&nbsp;Suyi Cao ,&nbsp;Raymond C. Koehler ,&nbsp;Krishnan M. Dhandapani ,&nbsp;Mohammad Badruzzaman Khan ,&nbsp;Pradip K. Kamat ,&nbsp;Ali Arbab ,&nbsp;David C. Hess ,&nbsp;Alison L. Herman ,&nbsp;Ligia Boisserand ,&nbsp;Lauren H. Sansing ,&nbsp;Andreia Morais ,&nbsp;Xuyan Jin ,&nbsp;Sanem Aykan ,&nbsp;Jaroslaw Aronowski","doi":"10.1016/j.neuropharm.2025.110801","DOIUrl":"10.1016/j.neuropharm.2025.110801","url":null,"abstract":"<div><div>Inflammation, particularly mediated through interleukin-6 (IL-6) signaling, plays a critical role in stroke pathophysiology. High levels of IL-6 are associated with poor outcomes in stroke patients. Therapeutic inhibition of IL-6 signaling may offer a novel strategy to mitigate post-stroke damage and improve recovery. This study evaluated the efficacy of tocilizumab (TCZ), a clinically approved monoclonal antibody that blocks IL-6 receptor signaling, using data from the Stroke Preclinical Assessment Network (SPAN), a multi-center, randomized, blinded, placebo-controlled trial in preclinical stroke models.</div></div><div><h3>Methods</h3><div>We analyzed behavioral and MRI morphometry data from 701 rodents (both males and females; 1:1), including healthy young mice, diet-induced obese mice, aging mice, and spontaneously hypertensive rats (SHR) treated with saline (N = 348) or TCZ (N = 353) at a dose of 100 mg/kg for mice, 10 mg/kg for rats after middle cerebral artery occlusion (MCAO).</div></div><div><h3>Results</h3><div>In the overall mouse cohort, TCZ did not significantly improve long-term sensorimotor recovery or reduce brain tissue loss measured by MRI. However, aging mice exhibited modest motor function improvements. In SHRs, TCZ treatment resulted in improved sensory-motor function, particularly in male rats, as demonstrated by enhanced corner test scores on days 7 and 28 post-MCAO. While TCZ in SHRs provided early (day 2) cerebroprotection with reduced lesion volume, it did not alter subsequent tissue loss, as measured by tissue atrophy at day 30.</div></div><div><h3>Conclusions</h3><div>These results suggest that IL-6R blockade with TCZ was associated with functional improvement in aging mice (modest) and hypertensive rats (notably males), without durable effect of brain tissue loss. No benefit was observed in the overall mouse cohort. These findings support IL-6 signaling as a viable therapeutic target and warrant further investigation into IL-6 receptor inhibition as a potential treatment strategy for stroke recovery.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110801"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701436","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":"Analgesic effect of cinobufagin is mediated by human-selective P2X7R antagonism governed by distinct extracellular domains","authors":"Kexin Yu ,&nbsp;Min Li ,&nbsp;Yuchen Jin,&nbsp;Miao Zhao,&nbsp;Zeliang Wang,&nbsp;Haibo Yu","doi":"10.1016/j.neuropharm.2025.110788","DOIUrl":"10.1016/j.neuropharm.2025.110788","url":null,"abstract":"<div><div>Chronic pain management remains a major clinical challenge, limited by the efficacy and safety profile of existing analgesics. The P2X7 receptor (P2X7R), a key driver of neuroinflammatory signaling, represents a promising therapeutic target; however, the clinical advancement of P2X7R antagonists has been hindered by limited efficacy and marked species differences in pharmacological activity. Here, we identify cinobufagin (CBG) as a novel, human-selective allosteric antagonist of P2X7R. CBG potently inhibited human P2X7R in functional assays measuring YO-PRO-1 uptake, calcium flux, and electrophysiological responses, but exhibited minimal activity against rat P2X7R or other P2X subtypes. Structural modeling and mutagenesis confirmed CBG's engagement with the canonical allosteric pocket, with residues F103 and M105 being critical for binding. Notably, species selectivity was determined not by variations within the binding pocket itself, but by distal extracellular domains. We further identified key discriminatory residues (R126, S165, I170, R270, Y288, N303) as novel molecular determinants of this selectivity. In a murine model of complete Freund's adjuvant (CFA)-induced inflammatory pain, CBG demonstrated significant analgesic efficacy. Comprehensive electrophysiological profiling also confirmed its selectivity against other major pain-related ion channels. Collectively, our work elucidates CBG's mechanism of action and reveals a paradigm in which allosteric modulation of P2X7R can be governed by long-range conformational influences from distal extracellular domains, rather than solely by direct ligand-pocket interactions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110788"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661622","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":"Chemogenetic activation of an A2 nucleus of the solitary tract to lateral parabrachial nucleus noradrenergic pathway blunts binge-like ethanol intake and promotes aversive unconditioned responses in male and female mice","authors":"Caryssa R. Drinkuth ,&nbsp;Ana Paula S. Dornellas ,&nbsp;Sara Guarino ,&nbsp;Montserrat Navarro ,&nbsp;Todd E. Thiele","doi":"10.1016/j.neuropharm.2025.110792","DOIUrl":"10.1016/j.neuropharm.2025.110792","url":null,"abstract":"<div><div>While there is strong evidence that the reinforcing effects of ethanol motivate seeking and consumption, ethanol produces aversive effects that limit consumption. We have previously found that in doses that support conditioned taste aversion (CTA) learning ethanol induces activity of noradrenergic (NE+) neurons of the A2 subregion of the nucleus of the solitary tract (NTS) as well as neurons within the lateral parabrachial nucleus (L-PBN), regions that have been implicated in integrating aversive responses. Here we provide evidence of a NE + circuit arising from the A2 and innervating the L-PBN in tyrosine hydroxylase (TH)-ires-cre mice. Next, we used male and female TH-ires-cre mice in tandem with an intersectional chemogenetic approach to assess the role of the NE + A2 to L-BPN circuit in modulating binge-like ethanol intake as well as unconditioned aversive behavior. Using “drinking in the dark” (DID) procedures we found that activating this circuit significantly blunted binge-like ethanol intake and associated blood ethanol concentrations (BECs) without altering sucrose solution intake. Furthermore, silencing this pathway during light cycle drinking revealed a trend of increased ethanol intake and an associated significant increase of BECs with no changes in sucrose intake. Additionally, activation of this circuit, as well as peripheral administration of the emetic agent LiCl, significantly increased the emission of mid-frequency vocalizations (MFVs) in mice, a phenotype reflecting aversive reactivity. The present findings provide novel evidence of a NE + A2 to L-PBN circuit in the modulation of binge-like ethanol intake and aversive responses.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110792"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687727","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}