Neuropharmacology最新文献

{"title":"Neurobiology, molecular pathways, and environmental influences in antisocial traits and personality disorders","authors":"Patryk M. Adamczyk ,&nbsp;Andrew Shaw ,&nbsp;Ilaria M. Morella ,&nbsp;Lorenzo More","doi":"10.1016/j.neuropharm.2025.110322","DOIUrl":"10.1016/j.neuropharm.2025.110322","url":null,"abstract":"<div><div>Personality disorders (PDs) are psychiatric conditions characterized by enduring patterns of cognition, emotion, and behaviour that deviate significantly from cultural norms, causing distress or impairment. The aetiology of PDs is complex, involving both genetic and environmental factors. Genetic studies estimate the heritability of PDs at 30%–60%, implicating genes involved in neurotransmitter regulation, such as those for serotonin transporters and dopamine receptors. Environmental factors, including childhood trauma and chronic stress, interact with genetic predispositions to induce epigenetic modifications like DNA methylation and histone modifications, contributing to PD development.</div><div>Neurobiological research has identified structural and functional abnormalities in brain regions related to emotional regulation and social cognition, such as the amygdala, prefrontal cortex, and limbic system. These abnormalities are linked to impaired emotion processing and interpersonal functioning in PDs. This review focuses on how environmental factors shape maladaptive behaviours and endophenotypes central to many PDs. It explores the interaction between the Ras-ERK, p38, and mTOR molecular pathways in response to environmental stimuli, and examines the role of oxidative stress and mitochondrial metabolism in these processes.</div><div>Also reviewed are various types of PDs and existing animal models that replicate key endophenotypes, highlighting changes in neurotransmitters and neurohormones. Identifying molecular biomarkers can lead to the development of “enviromimetic” drugs, which mimic environmental influences to activate molecular pathways, facilitating targeted, personalized treatments based on the molecular profiles of individuals with PDs. Ultimately, understanding the molecular mechanisms of PDs promises to enhance diagnostic accuracy, prognosis, and therapeutic outcomes for affected individuals.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110322"},"PeriodicalIF":4.6,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047162","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":"Sex-specific alterations in emotional behavior and neurotransmitter systems in LPA1 receptor-deficient mice","authors":"Laura Sánchez-Marín ,&nbsp;Violeta Jiménez-Castilla ,&nbsp;María Flores-López ,&nbsp;Juan A. Navarro ,&nbsp;Ana Gavito ,&nbsp;Eduardo Blanco-Calvo ,&nbsp;Luis J. Santín ,&nbsp;Francisco J. Pavón-Morón ,&nbsp;Fernando Rodríguez de Fonseca ,&nbsp;Antonia Serrano","doi":"10.1016/j.neuropharm.2025.110325","DOIUrl":"10.1016/j.neuropharm.2025.110325","url":null,"abstract":"<div><div>Lysophosphatidic acid (LPA) and the endocannabinoid system (ECS) are critical lipid signaling pathways involved in emotional regulation and behavior. Despite their interconnected roles and shared metabolic pathways, the specific contributions of LPA signaling through the LPA₁ receptor to stress-related disorders remain poorly understood. This study investigates the effects of LPA₁ receptor deficiency on emotional behavior and neurotransmitter-related gene expression, with a focus on sex-specific differences, using maLPA₁-null mice of both sexes. We hypothesized LPA₁ receptor loss disrupts the interplay between LPA and the endocannabinoid 2-arachidonoylglycerol (2-AG) signaling, resulting in distinct behavioral and molecular alterations. maLPA₁-null mice exhibited increased anxiety-like behaviors and altered stress-coping responses compared to wild-type counterparts, with more pronounced effects observed in females. Female mice also displayed higher corticosterone levels, though no genotype-related differences were observed. Plasma analyses revealed elevated LPA levels in maLPA₁-null mice, suggesting a compensatory mechanism, and reduced 2-AG levels, indicating impaired ECS signaling. Gene expression profiling in the amygdala and medial prefrontal cortex showed significant alterations in the gene expression of key components of LPA and 2-AG signaling pathways, as well as neuropeptide systems such as corticotropin-releasing hormone (CRH) and neuropeptide Y (NPY). Glutamatergic signaling components also exhibited sex-specific variations. These findings suggest that LPA₁ receptor deficiency impacts behavioral response and disrupts sex-specific neurotransmitter signaling, emphasizing the importance of LPA-ECS crosstalk in emotional regulation. This study provides insights into the molecular mechanisms underlying stress-related disorders such as depression and anxiety, which may inform the development of sex-specific therapeutic approaches.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110325"},"PeriodicalIF":4.6,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047259","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 characterization of the novel selective kappa opioid receptor agonists 10-Iodo-Akuammicine and 10-Bromo-akuammicine in mice","authors":"Kathryn Bland ,&nbsp;Chongguang Chen ,&nbsp;Peng Huang ,&nbsp;Conrad Ho ,&nbsp;Theodora Howe ,&nbsp;Katrina Ocampo ,&nbsp;Pingwei Zhao ,&nbsp;Simone Creed ,&nbsp;Joseph Noel-Torres ,&nbsp;Andrew P. Riley ,&nbsp;Lee-Yuan Liu-Chen","doi":"10.1016/j.neuropharm.2025.110316","DOIUrl":"10.1016/j.neuropharm.2025.110316","url":null,"abstract":"<div><div>Akuammicine (AKC), an indole alkaloid, is a kappa opioid receptor (KOR) full agonist with a moderate affinity. 10-Iodo-akuammicine (I-AKC) and 10-Bromo-akuammicine (Br-AKC) showed higher affinities for the KOR with K_i values of 2.4 and 5.1 nM, respectively, and high selectivity for the KOR over other opioid receptors. Both were KOR full agonists. As AKC and derivatives have distinctly different chemical structures from other KOR agonists, herein we investigated whether Br-AKC and I-AKC produced similar pharmacological effects as typical KOR agonists. Br-AKC and I-AKC inhibited compound 48/80-induced scratching in a dose-dependent manner, with ED₅₀ values of 3.0 and 1.3 mg/kg (s.c.), respectively, indicating anti-pruritic activities. Side effects of I-AKC and Br-AKC and their promotion of KOR phosphorylation and internalization were examined using doses in the effective anti-scratch dose range, at 1.9-3.8x ED₅₀ and 1.7-3.3x ED₅₀, respectively. At 5 mg/kg, Br-AKC and I-AKC produced profound conditioned place aversion (CPA). Br-AKC (10 mg/kg), but not I-AKC (5 mg/kg), reduced novelty-induced hyperlocomotion, and Br-AKC impaired rotarod performance more profoundly than I-AKC. Br-AKC, but not I-AKC, caused KOR phosphorylation at S369 in the mouse brain and KOR internalization in the ventral tegmental area. These results indicate that Br-AKC and I-AKC produce anti-scratch effect and CPA, similar to typical KOR agonists. However, there are some differences between the two. In addition, KOR phosphorylation and internalization in mouse brains are not associated with CPA but may be related to hypolocomotion and impaired rotarod performance. This is the first <em>in vivo</em> pharmacological characterization of AKC derivatives.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110316"},"PeriodicalIF":4.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040578","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":"Antisocial personality disorder:Failure to balance excitation/inhibition?","authors":"Klaus-Peter Lesch ,&nbsp;Nikita Gorbunov","doi":"10.1016/j.neuropharm.2025.110321","DOIUrl":"10.1016/j.neuropharm.2025.110321","url":null,"abstract":"<div><div>While healthy brain function relies on a dynamic but tightly regulated interaction between excitation (E) and inhibition (I), a spectrum of social cognition disorders, including antisocial behavior and antisocial personality disorder (ASPD), frequently ensuing from irregular neurodevelopment, may be associated with E/I imbalance and concomitant alterations in neural connectivity. Technological advances in the evaluation of structural and functional E/I balance proxies in clinical settings and in human cell culture models provide a general basis for identification of biomarkers providing a powerful concept for prevention and intervention across different dimensions of mental health and disease. In this perspective we outline a framework for research to characterize neurodevelopmental pathways to antisocial behavior and ASPD driven by (epi)genetic factors across life, and to identify molecular targets for preventing the detrimental effects of cognitive dysfunction and maladaptive social behavior, considering psychosocial experience; to validate signatures of E/I imbalance and altered myelination proxies as biomarkers of pathogenic neural circuitry mechanisms to determine etiological processes in the transition from mental health to antisocial behavior and ASPD and in the switch from prevention to treatment; to develop a neurobiologically-grounded integrative model of antisocial behavior and ASPD resultant of disrupted E/I balance, allowing to establish objective diagnoses and monitoring tools, to personalize prevention and therapeutic decisions, to predict treatment response, and thus counteract relapse; and finally, to promote transformation of dimensional disorder taxonomy and to enhance societal awareness and reception of the neurobiological basis of antisocial behavior and ASPD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110321"},"PeriodicalIF":4.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040542","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":"In vivo calcium extrusion from accumbal astrocytes reduces anxiety-like behaviors but increases compulsive-like responses and compulsive ethanol drinking in mice","authors":"Lee Peyton ,&nbsp;Humza Haroon ,&nbsp;Anthony Umpierre ,&nbsp;Hesham Essa ,&nbsp;Robert Bruce ,&nbsp;Long-Jun Wu ,&nbsp;Doo-Sup Choi","doi":"10.1016/j.neuropharm.2025.110320","DOIUrl":"10.1016/j.neuropharm.2025.110320","url":null,"abstract":"<div><div>The ventral striatum is crucially involved in reward processing. The present study investigates the behavioral effects of astrocyte-specific calcium extrusion virus “CalEx” on perseverative responses in the operant five-choice serial reaction time task and ethanol-conditioned place preference. Mice were injected with CalEx via the GfaABC₁D promoter to extrude cytosolic calcium from astrocytes within the ventral striatum. We found that CalEx transfection in the ventral striatum reduced evoked response duration, the maximum amplitude, and the response frequency to 500 μM ATP as measured by ΔF/F fluorescence intensity of the genetically encoded calcium indicator targeting astrocytes GCaMP6f. During the five-choice serial reaction time task, CalEx mice persisted in perseverative responses compared to their counterparts. Additionally, during ethanol-conditioned place preference, CalEx mice showed increased place preference for a low ethanol concentration compared to control group. Furthermore, we found that accumbal astrocytic calcium extrusion increased quinine adulterated ethanol drinking. Our findings suggest that diminishing ventral striatum astrocyte calcium activity contributes to compulsive behaviors, ethanol drinking, and enhanced ethanol drug reward.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110320"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024209","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":"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}