Colom-Rocha Carles, García-Fuster M Julia
IUNICS, University of the Balearic Islands, 07122 Palma, Spain.
Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, Spain.
Int J Neuropsychopharmacol. 2025 Sep 1;28(9). doi: 10.1093/ijnp/pyaf061.
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.
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).
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.
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.
乙醇的使用常常始于青春期，这是一个脆弱的发育阶段，存在大量神经重塑现象，特别会影响海马体的完整性，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影响，但很少有研究测量这两种药物在青少年时期同时使用以及成年后戒断和再次接触药物后的综合负面影响，因此这将是本研究的目的。
采用非条件范式，用乙醇、可卡因、二者组合或赋形剂对青春期的雄性和雌性斯普拉格 - 道利大鼠进行处理。在青春期、强制戒断期间以及成年后自愿接触乙醇后采集海马样本，通过蛋白质印迹法（死亡结构域相关蛋白[FADD]，以及神经丝轻链蛋白、NF-L和脑源性神经营养因子、BDNF之间的比率）评估神经毒性迹象，或通过免疫组织化学法（Ki-67、NeuroD）评估神经发生情况。
青春期乙醇通过降低FADD和增加NF-L/BDNF比率诱导海马体神经毒性，同时伴有NeuroD标记的神经元分化减少。这些影响在成年期戒断过程中恢复正常。成年大鼠自愿摄入乙醇后NeuroD减少，但仅在先前接触过青春期乙醇的大鼠中出现。青春期单独使用可卡因在任何检测的时间点均未引起任何变化。神经化学效应不受性别影响。有趣的是，NeuroD在青春期和成年期均成为乙醇毒性的生物标志物。
乙醇是一种神经毒性剂，青春期早期开始接触会加剧其毒性。我们的结论强化了避免和/或推迟首次接触乙醇年龄的建议，因为这会使其在日后生活中产生先前易感性影响。
