{"title":"Neurotoxic biomarkers of ethanol exposure: from adolescent vulnerability to adult voluntary intake in rats of both sexes.","authors":"Carles Colom-Rocha, M Julia García-Fuster","doi":"10.1093/ijnp/pyaf061","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Ethanol use is frequently initiated during adolescence, a vulnerable developmental period with a great deal of neuro-remodeling, specially affecting hippocampal integrity, and with a unique sensitivity to drug abuse. Previous data evaluated the neurochemical effects exerted by either ethanol or cocaine alone in the adolescent brain, but few studies measured the combined negative impact of both drugs immediate during adolescence and later following withdrawal and drug re-exposure in adulthood and therefore will be the aim of this study.</p><p><strong>Methods: </strong>Male and female Sprague-Dawley rats were treated in adolescence with non-contingent paradigms of ethanol, cocaine, their combination, or vehicle. Hippocampal samples were collected in adolescence, during forced withdrawal and following voluntary exposure to ethanol in adulthood to evaluate signs of neurotoxicity by western blot (Fas-Associated protein with Death Domain [FADD], and the ratio between Neurofilament light chain protein, NF-L, and Brain-Derived Neurotrophic Factor, BDNF) or neurogenesis by immunohistochemistry (Ki-67, NeuroD).</p><p><strong>Results: </strong>Adolescent ethanol induced hippocampal neurotoxicity by decreasing FADD and increasing NF-L/BDNF ratio, paired with decreased neuronal differentiation as labeled by NeuroD. These effects reverted to normal in adulthood during withdrawal. NeuroD was decreased after adult voluntary ethanol consumption, but exclusively in rats previously exposed to adolescent ethanol. Adolescent cocaine alone did not induce any changes at any time-points examined. The neurochemical effects were observed independently of sex. Interestingly, NeuroD emerged as a biomarker of ethanol toxicity both in adolescence and adulthood.</p><p><strong>Conclusions: </strong>Ethanol is a neurotoxic agent, and its toxicity is exacerbated by an early initiation during adolescence. Our conclusions reinforce the recommendation of avoiding and/or delaying the age of initial ethanol exposure, since it poses a prior vulnerability to its later impact in life.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449188/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Neuropsychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ijnp/pyaf061","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Ethanol use is frequently initiated during adolescence, a vulnerable developmental period with a great deal of neuro-remodeling, specially affecting hippocampal integrity, and with a unique sensitivity to drug abuse. Previous data evaluated the neurochemical effects exerted by either ethanol or cocaine alone in the adolescent brain, but few studies measured the combined negative impact of both drugs immediate during adolescence and later following withdrawal and drug re-exposure in adulthood and therefore will be the aim of this study.
Methods: Male and female Sprague-Dawley rats were treated in adolescence with non-contingent paradigms of ethanol, cocaine, their combination, or vehicle. Hippocampal samples were collected in adolescence, during forced withdrawal and following voluntary exposure to ethanol in adulthood to evaluate signs of neurotoxicity by western blot (Fas-Associated protein with Death Domain [FADD], and the ratio between Neurofilament light chain protein, NF-L, and Brain-Derived Neurotrophic Factor, BDNF) or neurogenesis by immunohistochemistry (Ki-67, NeuroD).
Results: Adolescent ethanol induced hippocampal neurotoxicity by decreasing FADD and increasing NF-L/BDNF ratio, paired with decreased neuronal differentiation as labeled by NeuroD. These effects reverted to normal in adulthood during withdrawal. NeuroD was decreased after adult voluntary ethanol consumption, but exclusively in rats previously exposed to adolescent ethanol. Adolescent cocaine alone did not induce any changes at any time-points examined. The neurochemical effects were observed independently of sex. Interestingly, NeuroD emerged as a biomarker of ethanol toxicity both in adolescence and adulthood.
Conclusions: Ethanol is a neurotoxic agent, and its toxicity is exacerbated by an early initiation during adolescence. Our conclusions reinforce the recommendation of avoiding and/or delaying the age of initial ethanol exposure, since it poses a prior vulnerability to its later impact in life.
背景：酒精的使用通常开始于青春期，这是一个脆弱的发育时期，具有大量的神经重塑，特别是影响海马的完整性，并且对药物滥用具有独特的敏感性。先前的数据评估了乙醇或可卡因单独对青少年大脑产生的神经化学作用，但很少有研究测量了这两种药物在青春期立即产生的负面影响，以及后来在成年期戒断和再次吸毒后产生的负面影响，因此这将是本研究的目的。方法：雄性和雌性Sprague-Dawley大鼠分别在青春期接受乙醇、可卡因、其组合或载体的非偶然范式治疗。在青春期、强制戒断期间和成年后自愿接触乙醇期间收集海马样本，通过western blot （FADD， NF-L/BDNF比率）或免疫组织化学（Ki-67, NeuroD）评估神经毒性迹象。结果：青少年乙醇通过降低FADD和增加NF-L/BDNF比值诱导海马神经毒性，并伴有NeuroD标记的神经元分化减少。这些影响在成年戒断期间恢复正常。成年自愿性乙醇摄入后，NeuroD减少，但仅限于先前暴露于青少年乙醇的大鼠。青少年单独服用可卡因在检查的任何时间点上都没有引起任何变化。观察到的神经化学效应与性别无关。有趣的是，NeuroD作为乙醇毒性的生物标志物出现在青春期和成年期。结论：乙醇是一种神经毒性物质，其毒性因青少年早期中毒而加剧。我们的结论强化了避免和/或推迟初次接触乙醇的年龄的建议，因为它对以后的生活影响有预先的脆弱性。
期刊介绍：
The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
