Neuropharmacology最新文献

{"title":"MK-801 attenuates one-trial tolerance in the elevated plus maze via the thalamic nucleus reuniens","authors":"Xue Xu ,&nbsp;Qian Gong ,&nbsp;Xiao-Dong Wang","doi":"10.1016/j.neuropharm.2025.110318","DOIUrl":"10.1016/j.neuropharm.2025.110318","url":null,"abstract":"<div><div>Anxiety, a future-oriented negative emotional state, is characterized by heightened arousal and vigilance. The elevated plus maze (EPM) test is a widely used assay of anxiety-related behaviors in rodents and shows a phenomenon where animals with prior test experience tend to avoid open arms in retest sessions. While this one-trial tolerance (OTT) phenomenon limits the reuse of the EPM test, the potential mechanisms remain unsolved. Here, we found that neither anxiogenic factors like acute restraint stress nor anxiolytic factors like diazepam (2 mg/kg) influenced the emergence of the OTT phenomenon in mice in the EPM test. In contrast, OTT was markedly attenuated by MK-801 (0.1 mg/kg), a non-competitive N-methyl-D-aspartate receptor antagonist. Through the use of c-fos mapping, MK-801 was found to increase neuronal activation in the thalamic nucleus reuniens (Re). Moreover, chemogenetic inactivation of Re neurons could prevent the effects of MK-801. Our findings suggest the Re as a crucial brain region in emotional adaptation in the EPM and shed light on the experimental design optimization and mechanistic investigation of anxiety-related behaviors.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110318"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024210","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":"The class-IIa HDAC inhibitor TMP269 promotes BMP-Smad signalling and is neuroprotective in in vitro and in vivo 6-hydroxydopamine models of Parkinson's disease","authors":"Adam G. O'Mahony ,&nbsp;Martina Mazzocchi ,&nbsp;Alex Morris ,&nbsp;Noelia Morales-Prieto ,&nbsp;Caitriona Guinane ,&nbsp;Sean L. Wyatt ,&nbsp;Louise M. Collins ,&nbsp;Aideen M. Sullivan ,&nbsp;Gerard W. O'Keeffe","doi":"10.1016/j.neuropharm.2025.110319","DOIUrl":"10.1016/j.neuropharm.2025.110319","url":null,"abstract":"<div><div>Degeneration of midbrain nigrostriatal dopaminergic neurons is a pathological hallmark of Parkinson's disease (PD). Peripheral delivery of a compound(s) to arrest or slow this dopaminergic degeneration is a key therapeutic goal. Pan-inhibitors of histone deacetylase (HDAC) enzymes, key epigenetic regulators, have shown therapeutic promise in PD models. However as there are several classes of HDACs (ClassI-IV), class-specific inhibition will be important to ensure target specificity. Here we examine the neuroprotective potential of the Class-IIa HDAC inhibitor, TMP269. We show that TMP269 protected against 6-hydroxydopamine (6-OHDA)-induced neurite injury in SH-SY5Y cells and cultured rat ventral mesencephalic dopaminergic neurons. We find that TMP269 upregulated the neurotrophic factor BMP2 and BMP-Smad dependent transcription signalling in SH-SY5Y cells, which was necessary for its neuroprotective effect against 6-OHDA-induced injury. Furthermore, peripheral continuous infusion of 0.5 mg/kg of TMP269 for 7 days via a mini-osmotic pump, reduced forelimb impairments induced by striatal 6-OHDA administration. TMP269 also protected dopaminergic neurons in the substantia nigra and their striatal terminals from striatal 6-OHDA-induced neurodegeneration and prevented the 6-OHDA-induced increases in the numbers of IBA1-positive microglia in the striatum and substantia nigra <em>in vivo</em>. TMP269 also prevented 6-OHDA-induced decreases in BMP2, pSmad1/5 and acetylated histone 3 levels, and it reversed 6-OHDA-induced increase in nuclear HDAC5 in dopaminergic neurons in the substantia nigra. These data add to the growing body of evidence that Class-IIa specific HDAC inhibitors may be pharmacological agents of interest for peripheral delivery with the goal of neuroprotection in PD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110319"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024212","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":"Exploring DMT: Endogenous role and therapeutic potential","authors":"Jakub Schimmelpfennig,&nbsp;Kamila Jankowiak-Siuda","doi":"10.1016/j.neuropharm.2025.110314","DOIUrl":"10.1016/j.neuropharm.2025.110314","url":null,"abstract":"<div><div>N,N-Dimethyltryptamine (DMT) is a naturally occurring amine and psychedelic compound, found in plants, animals, and humans. While initial studies reported only trace amounts of DMT in mammalian brains, recent findings have identified alternative methylation pathways and DMT levels comparable to classical neurotransmitters in rodent brains, calling for a re-evaluation of its biological role and exploration of this inconsistency. This study evaluated DMT's biosynthetic pathways, focusing on indolethylamine N-methyltransferase (INMT) and its isoforms, and possible regulatory mechanisms, including alternative routes of synthesis and how physiological conditions, such as stress and hypoxia influence DMT levels. This review considers the impact of endogenous regulatory factors on DMT synthesis and degradation, particularly under conditions affecting monoamine oxidase (MAO) efficiency and activity. We also examined DMT's potential roles in various physiological processes, including neuroplasticity and neurogenesis, mitochondrial homeostasis, immunomodulation, and protection against hypoxia and oxidative stress. DMT's lipophilic properties allow it to cross cell membranes and activate intracellular 5-HT2A receptors, contributing to its role in neuroplasticity. This suggests DMT may act as an endogenous ligand for intracellular receptors, highlighting its broader biological significance beyond traditional receptor pathways. The widespread evolutionary presence of DMT's biosynthetic pathways across diverse species suggests it may play essential roles in various developmental stages and cellular adaptation to environmental challenges, highlighting the neurobiological significance of DMT and its potential clinical applications. We propose further research to explore the role of endogenous DMT, particularly as a potential neurotransmitter.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110314"},"PeriodicalIF":4.6,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008888","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":"Characterization of a novel oronasal-restricted nicotine vaping self-administration model in mice","authors":"Lois S. Akinola ,&nbsp;Belle Buzzi ,&nbsp;Erin Kalck,&nbsp;Kimmie Le,&nbsp;Sarah Klein,&nbsp;Julian Vaughn,&nbsp;Jamil Basir,&nbsp;Justin Poklis,&nbsp;Paul Whiteaker,&nbsp;Keith L. Shelton,&nbsp;M. Imad Damaj","doi":"10.1016/j.neuropharm.2025.110315","DOIUrl":"10.1016/j.neuropharm.2025.110315","url":null,"abstract":"<div><div>Nicotine use remains one of the leading causes of preventable deaths in the United States and, while the prevalence of combustible cigarette use has declined over the past few years, the popularity of electronic nicotine delivery systems continues to rise. Vaping is not without risks, and its long-term effects, particularly in vulnerable populations, remain largely unknown. This study introduces a novel, oronasal-restricted, nicotine vapor self-administration mouse model to investigate the impact of nicotine concentration, genotype, sex, and age on self-administration and behavioral response to nicotine. Our studies show that male and female young adult mice respond to nicotine, demonstrating notable sex-related differences in intake, locomotor sensitization, and somatic withdrawal signs. In addition, we characterized intake in adolescent mice, showing sex differences as well. Finally, we showed genotype-related differences when using β2 knock-out mice, emphasizing the role of the β2 nAChR in nicotine reward and nicotine intake. This new model offers a more targeted approach to studying the potential risks of nicotine vaping in a more relevant and face-valid model compared to traditional whole-body nicotine vapor exposure in rodents.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110315"},"PeriodicalIF":4.6,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008886","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- and cytokine-dependent modulation of GABAergic transmission within the basolateral amygdala of male Sprague Dawley rats","authors":"Marvin R. Diaz,&nbsp;Thaddeus M. Barney,&nbsp;Paige Marsland,&nbsp;Terrence Deak","doi":"10.1016/j.neuropharm.2025.110304","DOIUrl":"10.1016/j.neuropharm.2025.110304","url":null,"abstract":"<div><div>Alcohol binge drinking has a multitude of effects on CNS function, including changes in inflammatory cytokines such as IL-6 and IL-1β that may contribute to mood fluctuations associated with the intoxication-withdrawal cycle. Widely throughout the brain, including the amygdala, IL-6 mRNA is enhanced during intoxication, whereas IL-1β is initially suppressed during alcohol intoxication, with increased expression seen shortly after ethanol clearance, during acute hangover. Furthermore, induction of neuroimmune genes appears to be muted during adolescence in the amygdala, suggesting a broader functional immaturity of the adolescent neuroimmune system in structures involved in negative affect associated with ethanol exposure. However, neither the effect of IL-6 or IL-1β on synaptic function within the amygdala nor the impact of acute intoxication and withdrawal on these cytokines’ function are known. To test this, we used whole-cell patch-clamp electrophysiology to assess the effects of IL-6 and IL-1β on GABA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in BLA pyramidal neurons from male rats in early adolescence (P28-40) or adulthood (P70+). These experiments were done in naïve, intoxicated (3–4 h following an intraperitoneal injection of 3.5 g/kg ethanol), and during acute hangover (11–18 h post ethanol injection). In naïve males, we found that IL-6 (10 ng/ml) significantly enhanced sIPSC amplitude only in adults, with no apparent effect in adolescents; this effect of IL-6 in adults was not different during intoxication. Conversely, IL-1β (10 ng/ml) did not alter sIPSC frequency in any group (naïve or hangover adolescents or adults). Unlike our previous work in adult rats, here we found that contextual fear conditioning was not altered in adolescents when conditioned during acute hangover. Together, these observations suggest that IL-6, but not IL-1β, regulation of BLA GABA transmission emerges as a function of age, but is not affected by acute ethanol exposure or hangover for adolescents or adults. Importantly, these findings provide additional evidence to support functional immaturity of the neuroimmune system in adolescence.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110304"},"PeriodicalIF":4.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008892","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":"Synaptic protein expression in bipolar disorder patient-derived neurons implicates PSD-95 as a marker of lithium response","authors":"Kayla E. Rohr ,&nbsp;Himanshu K. Mishra ,&nbsp;Johansen Amin ,&nbsp;Timothy Nakhla ,&nbsp;Michael J. McCarthy","doi":"10.1016/j.neuropharm.2025.110313","DOIUrl":"10.1016/j.neuropharm.2025.110313","url":null,"abstract":"<div><div>Bipolar disorder (BD) is a severe mental illness characterized by recurrent episodes of depression and mania. Lithium is the gold standard pharmacotherapy for BD, but outcomes are variable, and the relevant therapeutic mechanisms underlying successful treatment response remain uncertain. To identify synaptic markers of BD and lithium response, we measured the effects of lithium on induced pluripotent stem cell-derived neurons from BD patients and controls. We determined that baseline expression of synapsin I (SYN1) and PSD-95 is reduced in BD neurons compared to controls. In control neurons, lithium treatment had modest, transient effects increasing SYN1 and PSD-95 expression. In BD neurons, lithium increased SYN1 expression regardless of lithium response history. However, lithium only increased PSD-95 expression selectively in neurons from lithium-responders and not in neurons from lithium non-responders, leading to group differences in the colocalization of SYN1 and PSD-95. In conclusion, this preliminary work indicates synaptic protein markers are associated with BD pathology and correction of post-synaptic protein expression may be an important mechanism underlying lithium response.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110313"},"PeriodicalIF":4.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008890","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":"Swietenolide inhibits the TXNIP/NLRP3 pathways via Nrf2 activation to ameliorate cognitive dysfunction in diabetic mice","authors":"Xinquan Song ,&nbsp;Siwen Fan ,&nbsp;Yuetong Gao,&nbsp;Anxin Ma,&nbsp;Xiashu Zhang,&nbsp;Zihui Zhou,&nbsp;Yijia Zheng,&nbsp;Lei Du,&nbsp;Xia Zhu","doi":"10.1016/j.neuropharm.2025.110312","DOIUrl":"10.1016/j.neuropharm.2025.110312","url":null,"abstract":"<div><div>Oxidative stress and inflammation play important roles in diabetic-associated cognitive dysfunction (DACD). Swietenolide (Std), isolated from the fruit of Swietenia macrophylla King, exhibits various potent pharmacological activities, including antioxidant, anti-inflammatory, and anti-tumor properties. However, the effects of Std on DACD remains unexplored. We utilized diabetic <em>db/db</em> mice and the hippocampal cell line HT22 to evaluate the effects and underlying molecular mechanisms of Std on DACD. Molecular docking study, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay analyses were conducted to elucidate the molecular mechanisms involved. We found that Std significantly improved cognitive dysfunction in diabetic mice and increased cell viability in HT22 cells under high glucose condition. The reduction in superoxide dismutase (SOD) enzamy activity and glutathione (GSH) level, along with an increase in malondialdehyde (MDA) induced by high glucose in hippocampus, were reversed by Std treatment. Furthermore, Std effectively diminished the levels of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Importantly, Std markedly activated the Nrf2 pathway to inhibit the thioredoxin-interacting protein/NOD-like receptor protein 3 (TXNIP/NLRP3) pathways. However, the neuroprotective effect of Std was significantly weakened by Nrf2 inhibitor ML385. These results indicate that Std provides substantial protection against high glucose-induced hippocampal injury by inhibiting the TXNIP/NLRP3 pathways dependent on Nrf2, which may serve as a promising agent for attenuating DACD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110312"},"PeriodicalIF":4.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008908","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":"Restorative properties of chronic lurasidone treatment on emotional dysfunction in rats exposed to chronic unavoidable stress: A role for medial prefrontal cortex - nucleus accumbens network","authors":"Eleonora Corridori ,&nbsp;Sara Salviati ,&nbsp;Veronica Begni ,&nbsp;Alessia Marchesin ,&nbsp;Carla Gambarana ,&nbsp;Marco Andrea Riva ,&nbsp;Simona Scheggi","doi":"10.1016/j.neuropharm.2025.110302","DOIUrl":"10.1016/j.neuropharm.2025.110302","url":null,"abstract":"<div><div>Anhedonia, a transdiagnostic symptom prevalent in depressive and psychotic disorders, poses a significant challenge for pharmacological intervention due to its association with impaired motivation. Understanding how psychotropic drugs can modulate this pathological domain and elucidating the molecular mechanisms underlying such effects are crucial endeavors in psychiatric research. In this study, we aimed to investigate the pro-motivational properties of lurasidone in a rat (Sprague Dawley males) model of anhedonia and to unravel the interplay between lurasidone and the brain regions critical for reward processing. Exposure to unpredictable chronic stress (UCS) led to a marked reduction in motivation, a deficit that was restored by lurasidone treatment at 3 mg/kg, but not at 10 mg/kg. Interestingly, the stress-induced decrease in reactivity to negative stimuli was reversed by both doses of lurasidone. At the molecular level, stressed animals exhibited reduced expression of neuroplastic markers, that was increased following lurasidone administration. Furthermore, UCS exposure impaired the activation of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in response to hedonic stimuli, an effect amended by lurasidone treatment. Additionally, lurasidone restored the impaired phosphorylation of DARPP-32, a key regulator of dopamine signaling, in mPFC and NAc of UCS rats exposed to a hedonic stimulus.</div><div>These findings underscore the potential of lurasidone in improving various psychopathological domains, like impaired motivation and emotional reactivity, core elements contributing to the disability associated with mental disorders. These effects highlight the therapeutic potential of lurasidone in addressing the intricate behavioral and neurochemical alterations associated with anhedonia and related mood disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110302"},"PeriodicalIF":4.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008904","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":"CD38-mediated oxytocin signaling in paraventricular nucleus contributes to empathic pain","authors":"Xinying Zhang ,&nbsp;Zifeng Wu ,&nbsp;Siqi Yang ,&nbsp;Yuanyuan Wang ,&nbsp;Suwan Hu ,&nbsp;Yawei Ji ,&nbsp;Qi Zhang ,&nbsp;Yuchen Bu ,&nbsp;Chenqi Jiang ,&nbsp;Jingyao Huang ,&nbsp;Haoran Wang ,&nbsp;Di Wang ,&nbsp;Chaoli Huang ,&nbsp;Peng Jiang ,&nbsp;Cunming Liu ,&nbsp;Xiaolin Yang ,&nbsp;Chun Yang ,&nbsp;Ling Yang ,&nbsp;Riyue Jiang","doi":"10.1016/j.neuropharm.2025.110301","DOIUrl":"10.1016/j.neuropharm.2025.110301","url":null,"abstract":"<div><div>Empathy plays a crucial role in social communication and the perception of affective states and behavioral processes. In this study, we observed that empathic interaction with a mouse experiencing pain resulted in decreased mechanical pain thresholds and anxiety-like behaviors in its bystander, though the underlying mechanisms remain unknown. We demonstrated that CD38 expression in the paraventricular nucleus (PVN) was upregulated during empathic pain, and the pain and emotions of CD38 knockout (CD38KO) mice as bystanders were not affected. Furthermore, fiber photometry recordings indicated that calcium activities of PVN neurons were increased during empathic pain. Interestingly, direct chemogenetic inhibition of PVN neurons attenuated the hyperalgesia and anxiety-like behaviors associated with empathic pain. In contrast, activating PVN neurons through chemogenetics in CD38KO mice induced hyperalgesia and anxiety-like effects in empathic pain. Oxytocin levels in PVN were upregulated during empathic pain, while CD38KO mice inhibit the upregulation in OXT levels, confirming that CD38 is involved in releasing brain OXT and that the CD38-OXT system in the PVN plays a role in empathic pain. Collectively, CD38-mediated oxytocin signaling in PVN is closely linked to empathic pain through its effect on the activation of PVN neurons, and it could be viable targets for novel empathic behavior interventions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110301"},"PeriodicalIF":4.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008897","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 chronic ethanol exposure on dorsal medial striatal neurons receiving convergent inputs from the orbitofrontal cortex and basolateral amygdala","authors":"Sudarat Nimitvilai-Roberts ,&nbsp;Marcelo F. Lopez ,&nbsp;John J. Woodward","doi":"10.1016/j.neuropharm.2025.110303","DOIUrl":"10.1016/j.neuropharm.2025.110303","url":null,"abstract":"<div><div>Alcohol use disorder is associated with altered function of cortical-amygdala-striatal circuits such as the orbitofrontal cortex (OFC), basolateral amygdala (BLA) and their connections to the dorsal medial striatum (DMS) shown to be involved in goal-directed actions. Using retrobead tracing, we previously reported enhanced excitability of DMS-projecting OFC neurons in mice following 3-to-7-day withdrawal from chronic intermittent ethanol (CIE) exposure. In the same animals, spiking of DMS-projecting BLA neurons was decreased at 3-days post-withdrawal followed by an increase in firing at 7- and 14-days. In the current study, we used transsynaptic labeling and slice electrophysiology to investigate the effects of CIE exposure on DMS neurons that receive convergent inputs from the OFC and BLA. Mice were infused with anterograde transsynaptic AAVs in the OFC (AAV1-Cre) and BLA (AAV1-Flpo) and a Cre-On/Flp-On-YFP AAV in the DMS followed by 4 weekly cycles of Air or CIE vapor exposure. Current-clamp recordings of YFP + DMS^OFC−BLA neurons showed three distinct patterns of firing: regular spiking, regular spiking followed by depolarization block and regular spiking with the appearance of broadened action potentials and plateau potentials at higher current steps (termed FANS). In both male and female mice, withdrawal from CIE exposure significantly increased the excitability of regular spiking neurons as compared to air controls. More subtle effects were observed on FANS neurons with both increases and decreases in firing that were current step and sex-dependent. These findings add to a growing literature demonstrating how neurons within cortical-amygdala-striatal circuits implicated in compulsive/habitual behaviors are impacted by chronic alcohol exposure.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110303"},"PeriodicalIF":4.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008900","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}