Neuropharmacology最新文献

{"title":"Preoperative sleep deprivation prolongs postoperative hyperalgesia by downregulating spinal cord D2R expression via the PP2A/AKT-dependent NMDA receptor phosphorylation.","authors":"Qi Liu, Qingyue Dong, Tianwei Xu, Yang Jiao, Jiacheng Yu, Wei Zhang, Xiaoping Gu, Yulin Huang, Rui Xu, Zhengliang Ma","doi":"10.1016/j.neuropharm.2026.111233","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2026.111233","url":null,"abstract":"<p><p>Preoperative sleep deprivation (SD) is known to exacerbate postoperative pain, but the underlying mechanisms remain unclear. Using a male mouse model of 48-hour continuous SD followed by incisional surgery, we found that SD alone induced transient mechanical hyperalgesia, and when combined with surgery (SI group) it significantly aggravated and prolonged postoperative pain recovery until day 10. On postoperative day 7, SI mice showed marked downregulation of spinal dopamine D2 receptor (D2R) expression and decreased spinal dopamine concentration. D2R was predominantly expressed on spinal glutamatergic neurons. Overexpression of D2R on these neurons via intrathecal AAV injection effectively alleviated the prolonged hyperalgesia, normalizing pain sensitivity by day 7. Mechanistically, D2R downregulation led to increased phosphorylation of NMDA receptor subunits (p-NR1 and p-NR2B) without altering total NMDA receptor levels. Co-immunoprecipitation revealed an interaction between D2R and protein phosphatase 2A (PP2A). SI mice exhibited decreased PP2A expression but increased p-AKT, p-GSK3β, and β-catenin, indicating activation of the PP2A/AKT signaling pathway, which were reversed by D2R overexpression. Furthermore, pharmacological activation of PP2A with DT-061 not only downregulated p-AKT, p-GSK3β, β-catenin, p-NR1 and p-NR2B, but also produced significant analgesia in SI mice. Collectively, these results demonstrate that preoperative sleep deprivation prolongs postoperative hyperalgesia by downregulating spinal D2R on glutamatergic neurons, which disinhibits the PP2A/AKT pathway and enhances NMDA receptor phosphorylation. Targeting D2R or its downstream PP2A/AKT signaling may represent a novel therapeutic strategy for managing persistent postoperative pain caused by preoperative sleep deprivation in male mice.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"111233"},"PeriodicalIF":4.7,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228223","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":"Subanesthetic ketamine modulates region-specific neural and endocrine responses to acute stress in rats.","authors":"U S Drozd, V V Bulygina, G T Shishkina, T S Kalinina, N N Dygalo, D A Lanshakov","doi":"10.1016/j.neuropharm.2026.111231","DOIUrl":"10.1016/j.neuropharm.2026.111231","url":null,"abstract":"<p><p>Exposure to acute, inescapable stress triggers a coordinated neural and endocrine response across corticolimbic and brainstem circuits. Although subanesthetic ketamine has rapid antidepressant effects, it is unclear whether its modulation of the stress-response network depends on the presence of an acute stressor. In this study, naïve rats received subanesthetic ketamine (15 mg/kg) or a vehicle, and then underwent the tail suspension test (TST) or remained undisturbed in their home cages. Ketamine reduced immobility in the TST and attenuated the stress-induced increase in plasma corticosterone levels. Regional c-Fos expression, ascertained through quantitative real-time PCR and immunohistochemistry, revealed region-specific and context-dependent modulation. Ketamine selectively activated neuronal populations in the prefrontal cortex and potentiated stress-induced activation in the hippocampus and dorsal raphe nucleus. However, it suppressed stress-driven hyperactivation in the amygdala and elicited non-additive activation patterns in the brainstem. These findings suggest that subanesthetic ketamine modulates the regional balance of neuronal activation and attenuates hypothalamic-pituitary-adrenal axis reactivity in a state-dependent manner. Furthermore, its effects on the stress-response network are influenced by the presence of an acute stressor.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"111231"},"PeriodicalIF":4.7,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224717","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":"zDHHC11 is a common palmitoyltransferase regulating microglia-mediated neuroinflammation across neurodegenerative diseases.","authors":"Haiting Luo, Diandian Jiang, Zhiyuan Hao, Jie Bu, Jiayi Wang, Nuo Xu, Xuan Nie, Yanjun Zhang, Qingsheng Yin, Pengwei Zhuang","doi":"10.1016/j.neuropharm.2026.111226","DOIUrl":"10.1016/j.neuropharm.2026.111226","url":null,"abstract":"<p><strong>Purpose: </strong>Microglia-mediated neuroinflammation is a shared feature across Alzheimer's disease (AD), Parkinson's disease (PD), and diabetic cognitive impairment (DCI), but the convergent molecular mechanisms remain unclear. This study investigated whether protein S-palmitoylation serves as a common regulator of microglial neuroinflammation across distinct neurodegenerative diseases etiologies and aimed to identify the key palmitoyltransferase involved.</p><p><strong>Methods: </strong>In vivo ND models (APP/PS1 for AD, MPTP for PD, STZ/high-fat diet for DCI) and in vitro BV2 microglial models stimulated with amyloid-β (Aβ), lipopolysaccharide (LPS), or high glucose (HG) were established. Microglial morphology, inflammatory responses, and the TLR4/MyD88 pathway were assessed by immunofluorescence, RNA-seq, RT-qPCR, and ELISA. Protein palmitoylation levels were evaluated using 2-BP and ABE assays. Palmitoyltransferase expression profiling was performed, and protein-level validation was conducted both in vitro and in vivo. Subsequently, the identified common enzyme, zDHHC11, was knocked down by siRNA to determine its functional role.</p><p><strong>Results: </strong>All three ND models showed robust microglial activation with a pro-inflammatory amoeboid morphology. Aβ, LPS, and HG each upregulated pro-inflammatory cytokines and activated the TLR4/MyD88 pathway in BV2 cells. Palmitoylation inhibition with 2-BP attenuated cytokine production, and all three stimuli increased total protein palmitoylation. Among all palmitoyltransferases screened, zDHHC11 was uniquely and consistently upregulated by all three stimuli. This upregulation was further corroborated at the protein level, with elevated zDHHC11 expression observed both in cultured cells and in brain tissue sections. Knockdown of Zdhhc11 suppressed cytokine expression/secretion and reduced TLR4/MyD88 levels, indicating that zDHHC11 acts upstream of this common pathway.</p><p><strong>Conclusion: </strong>Protein S-palmitoylation mediated by zDHHC11 is a convergent mechanism driving microglial pro-inflammatory activation across distinct ND etiologies. zDHHC11 represents a common regulator of TLR4/MyD88-dependent neuroinflammation and a potential therapeutic target for multiple NDs.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"111226"},"PeriodicalIF":4.7,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207601","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":"Cholinergic-dependent metaplasticity in the amygdala-insula pathway during incubation of cocaine craving.","authors":"Adélie Salin, Virginie Lardeux, Emilie Dugast, Eric Balado, Nathalie Thiriet, Mohamed Jaber, Marcello Solinas, Pauline Belujon","doi":"10.1016/j.neuropharm.2026.111232","DOIUrl":"10.1016/j.neuropharm.2026.111232","url":null,"abstract":"<p><p>The time-dependent increase in drug seeking during abstinence, termed 'incubation of craving' is believed to play a major role in the persistent risks of relapse. This phenomenon is associated with synaptic plasticity changes across brain structures involved in reward processing, executive functions, emotion regulation and inhibitory control. The basolateral amygdala (BLA) and the anterior insular cortex (aIC) are two interconnected structures involved in processing internal and external drug-related cues and are known to play a role in drug craving. However, whether chronic cocaine alters synaptic plasticity within the BLA-aIC circuit and how these changes evolve during abstinence remains unclear. Here, using cocaine self-administration and in vivo electrophysiological recordings in anesthetized male rats, we demonstrate that, while long-term potentiation in the BLA-aIC pathway remains intact, long-term depression is disrupted throughout abstinence in both cocaine- and sucrose-rats, indicating a persistent impairment in synaptic weakening mechanisms. Importantly, a loss of depotentiation was observed after late but not early abstinence, and was specific to cocaine self-administration, identifying it as a hallmark of incubation of craving. Systemic, but not local intra-aIC, blockade of muscarinic receptors with atropine restored depotentiation and reduced cocaine-seeking behavior. Finally, qPCR analysis revealed region-specific transcriptional adaptations, with upregulation of muscarinic, NMDA and AMPA receptor transcripts in the BLA and a selective decrease of Grin2a in the aIC. Together, these findings point to cholinergic regulation of BLA-aIC metaplasticity as a candidate mechanism underlying incubation of cocaine craving.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"111232"},"PeriodicalIF":4.7,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216458","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":"Therapeutic potential and toxicological trade-offs of nanoparticle-enhanced valproic acid in glioblastoma: Behavioral and oxidative insights.","authors":"Negin Khodayari, Farnaz Sedghy, Mehdi Ranjbar, Pouya Pashazadeh Azari, Fatemeh Houshmand, Azadeh Shahrokhi Raeini, Merat Mahmoodi, Hamideh Bashiri, Reza Kheirandish","doi":"10.1016/j.neuropharm.2026.111230","DOIUrl":"10.1016/j.neuropharm.2026.111230","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) is a highly aggressive brain tumor with a poor prognosis. In the current research, the therapeutic and behavioral efficacy of valproic acid (VPA) and its nanoparticles (Nano VPA) with or without temozolomide (TMZ) was investigated in the C6 glioblastoma rat model.</p><p><strong>Methods: </strong>We divided eighty-four adult male Wistar rats into seven groups (n = 12/group): sham, tumor, TMZ, VPA, nano VPA, VPA + TMZ, and nano VPA + TMZ. To induce tumors, C6 cells were injected into the brains of the rats. On days 12 to 15, behavioral performance was assessed using the social interaction test, elevated plus maze, open field, rotarod, and passive avoidance. On day 18, tumor size, edema, and histopathology were examined. Oxidative stress parameters in brain tissue and serum were measured by ELISA.</p><p><strong>Results: </strong>VPA and Nano VPA significantly inhibited tumor growth, either alone or with TMZ. All treatments except Nano VPA + TMZ improved survival compared with tumor controls. Treated groups showed enhanced anxiety regulation, sociability, learning, and memory. Motor coordination improved following VPA or Nano VPA therapy. Tumor induction reduced serum SOD, CAT, and TAC levels; treatments raised serum TAC and lowered brain MDA, but further reduced serum SOD.</p><p><strong>Conclusion: </strong>Our results suggest that oxidative stress modulation may contribute to the neurobehavioral and antitumor effects of both VPA and nano-VPA. While nano-VPA showed greater tumor reduction, conventional VPA was more effective in improving survival. Combining VPA with TMZ may enhance outcomes, and support further study of Nano VPA as an adjuvant therapy for GBM.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"111230"},"PeriodicalIF":4.7,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216545","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":"N-acetylcysteine decreases toluene conditioned place preference and modulates corticostriatal activity in adolescent rats.","authors":"Ajina C Carampel, Joannes Luke B Asis, Johanna C Munar, Cynthia Grace C Gregorio, Paul Mark B Medina, Gregory J Quirk, Rohani Cena-Navarro","doi":"10.1016/j.neuropharm.2026.111224","DOIUrl":"10.1016/j.neuropharm.2026.111224","url":null,"abstract":"<p><p>Inhalant (toluene) use disorder (IUD) continues to be a public health problem especially among Filipino adolescents. Animal models of IUD have not yet explored neurobiological changes from chronic toluene exposure, or possible treatments for long-lasting toluene-induced deficits. In rats repeatedly exposed to 3000 ppm of toluene vapor over 12 days, we report that daily administration of N-acetylcysteine (NACys; 100 mg/kg i.p. or 0.9 g/l oral), but not melatonin (10 mg/kg i.p.), during 8 days of abstinence reduced toluene conditioned place preference in both male and female adolescent Sprague Dawley rats. Using immunofluorescence, we found that toluene-exposed rats showed decreased c-Fos densities in the dorsomedial striatum (DMS), dorsolateral striatum, and ventrolateral orbitofrontal cortex (vlOFC) after 8 days of abstinence. NACys partially rescued c-Fos expression in vlOFC. We found that c-Fos densities in both vlOFC and prelimbic cortex were significantly correlated with CPP values and with c-Fos densities in the DMS across treatment groups, suggesting that a history of toluene exposure may act by reducing cortical modulation of the dorsal striatum to promote long-lasting drug context seeking. Our findings suggest that NACys may be a promising treatment for IUD in adolescent males and females.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"111224"},"PeriodicalIF":4.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195825","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":"Global Malat1 deletion in two genetic mouse models reveals sex-dependent effects on select ethanol-related behaviors.","authors":"Daniela V Gil, Annalisa M Baratta, Carolyn Ferguson, Martha Miskanic, Andrew Iker, Gregg E Homanics, Sean P Farris","doi":"10.1016/j.neuropharm.2026.111215","DOIUrl":"10.1016/j.neuropharm.2026.111215","url":null,"abstract":"<p><p>Alcohol use disorder (AUD) is a widespread psychiatric condition, yet the molecular mechanisms underlying its development remain poorly understood. While prior studies have largely focused on protein-coding genes, long non-coding RNAs (lncRNAs) remain underexplored in AUD. Malat1, a highly abundant and evolutionarily conserved lncRNA, is elevated in post-mortem brain tissue of human AUD subjects and rodents chronically exposed to ethanol; however, its causal contribution to AUD-relevant behaviors remains unknown. Using CRISPR/Cas9 genome editing, we generated two complementary global Malat1 knockout mouse models to assess its role in ethanol intake and related phenotypes. Constitutive knockout selectively attenuated acute functional tolerance rate and every-other-day two-bottle-choice (EOD-2BC) ethanol intake in females. These results were supported by an inducible adult conditional global knockout model, which reduced EOD-2BC ethanol consumption in females without altering taste preference. Together, our findings provide the first causal evidence that Malat1 regulates select ethanol-related behaviors in a sex-specific manner, supporting further investigation into its underlying mechanisms in AUD.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"111215"},"PeriodicalIF":4.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167957","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":"Activation of a locus coeruleus to ventral tegmental area noradrenergic pathway blunts binge-like ethanol intake and promotes aversive unconditioned responses in TH-ires-Cre mice","authors":"Caryssa R. Drinkuth ,&nbsp;Ana Paula S. Dornellas ,&nbsp;Montserrat Navarro ,&nbsp;Todd E. Thiele","doi":"10.1016/j.neuropharm.2026.110864","DOIUrl":"10.1016/j.neuropharm.2026.110864","url":null,"abstract":"<div><div>Ethanol comprises innately aversive properties that may act as a deterrent to overconsumption. We have previously found that chemogenetic activation or inhibition of a noradrenergic locus coeruleus (LC) to rostromedial tegmental nucleus (RMTg) pathway bidirectionally modulates binge-like ethanol intake and aversive reactivity in male and female TH-<em>ires</em>-Cre mice. We previously hypothesized that noradrenergic RMTg circuitry may modulate ethanol intake and aversion through inhibitory inputs to the ventral tegmental area (VTA), a region that is both densely innervated by the RMTg and proposed to coordinate the balance between the rewarding and aversive properties of ethanol. Here, we build upon this work by providing evidence for a direct role of noradrenergic signaling in the VTA in the modulation of binge-like ethanol intake and unconditioned aversive responses. Using “drinking-in-the-dark” procedures, we reveal that site-directed administration of an α-1 adrenergic receptor (AR) agonist into the VTA blunts binge-like ethanol intake and associated blood ethanol concentrations (BECs) without altering sucrose consumption or locomotion. Next, we demonstrate that chemogenetic activation of noradrenergic LC to VTA projection neurons blunts binge-like ethanol intake and BECs in male and female mice without altering sucrose intake or locomotion. Further, we demonstrate that chemogenetic activation of LC to VTA projection neurons induces mid-frequency vocalizations consistent with an aversion- or malaise-like state in mice. The present findings indicate an important involvement of noradrenergic LC to VTA circuitry in the modulation of ethanol intake and aversion.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"289 ","pages":"Article 110864"},"PeriodicalIF":4.6,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102668","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":"Discovery of a novel IMS48 as a dual inhibitor of acetylcholinesterase and butyrylcholinesterase: In vitro and in vivo study for Alzheimer therapy","authors":"Samman Munir ,&nbsp;Zunera Chauhdary ,&nbsp;Imran Ahmad Khan ,&nbsp;Matloob Ahmad ,&nbsp;Mohsin Khurshid ,&nbsp;Usman Ali Ashfaq","doi":"10.1016/j.neuropharm.2026.110856","DOIUrl":"10.1016/j.neuropharm.2026.110856","url":null,"abstract":"<div><div>Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC₅₀ values of 0.31 ± 0.04 μM and 1.85 ± 0.05 μM, respectively, outperforming the standard drug donepezil. In the in vivo study, rats were administered D-gal (300 mg/kg) and AlCl₃ (150 mg/kg) orally for three weeks to induce AD-like symptoms. Concurrently, IMS48 was administered at doses of 0.75 mg/kg and 1.5 mg/kg for 21 days. Donepezil (DON) was used as a positive control to evaluate the therapeutic efficacy of the IMS8 compound. IMS48 treatment significantly reversed behavioral alterations and improved learning ability. Histopathological analysis demonstrated that IMS48 effectively inhibited neuronal death and neurofibrillary tangles in the brain tissue. Furthermore, IMS48 restored the altered antioxidant enzyme levels (p &lt; 0.001), reducing malondialdehyde (MDA) concentration and enhancing superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) concentrations. IMS48 also downregulated the gene expression of AChE (1.56 ± 0.10-fold and 1.71 ± 1.76-fold), APP (1.96 ± 0.17-fold and 3.39 ± 0.139-fold), BACE1 (1.92 ± 0.10-fold and 2.59 ± 0.04-fold), TNFα (2.16 ± 0.21-fold and 3.35 ± 0.17-fold), IL-1α (1.86 ± 0.236-fold and 2.56 ± 0.15-fold), and IL-1β (1.58 ± 1.82-fold and 2.32 ± 0.13-fold), associated with AD pathology and neuroinflammation. Overall, these findings highlight the neuroprotective potential of IMS48 in enhancing cognitive function and mitigating neurodegeneration in AD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"289 ","pages":"Article 110856"},"PeriodicalIF":4.6,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106459","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":"Pharmacological modulation of wakefulness and extracellular hypothalamic histamine release in adult male mice using TAK-925, modafinil, pitolisant, MK-8133 and Lu AF11167","authors":"Camille G. Hviid ,&nbsp;Gunnar Sørensen ,&nbsp;Birgitte R. Kornum ,&nbsp;Kjartan F. Herrik","doi":"10.1016/j.neuropharm.2026.110862","DOIUrl":"10.1016/j.neuropharm.2026.110862","url":null,"abstract":"<div><div>Histamine is a key regulator of wake and arousal, however its role in pharmacological modulation of wake is largely unknown. Specifically, whether histamine is always activated during pharmacologically induced wake promotion or even necessary for wake remains unclear. This study therefore measured EEG/EMG and accelerometer activity to determine sleep/wake states and locomotor activity and determined extracellular hypothalamic histamine levels using microdialysis following treatment with five wake- and sleep-modulatory compounds. We investigated the effects of three presumed wake-promoting compounds TAK-925 (danavorexton), modafinil and pitolisant as well as two presumed sleep-inducing compounds MK-8133 and Lu AF11167 in adult male mice. TAK-925 and modafinil dose-dependently prolonged wakefulness, whereas pitolisant had no effect. In contrast, TAK-925 and pitolisant increased extracellular histamine levels in hypothalamus, whereas modafinil had no effect. MK-8133 and Lu AF11167 both reduced wakefulness and decreased extracellular hypothalamic histamine levels. In vehicle-treated male mice, histamine levels were correlated with wakefulness but in pharmacologically treated male mice, this correlation was decoupled. These data demonstrate that wake can be modulated without modulating histamine signaling and vice versa.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"289 ","pages":"Article 110862"},"PeriodicalIF":4.6,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100569","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}