Okhuarobo Agbonlahor, Bolton Jessica L, Igbe Ighodaro, Zorrilla Eric P, Baram Tallie Z, Contet Candice
The Scripps Research Institute, Department of Molecular Medicine, La Jolla, CA, USA.
University of Benin, Faculty of Pharmacy, Department of Pharmacology & Toxicology, Benin City, Nigeria.
Neurobiol Stress. 2020 Nov 30;13:100269. doi: 10.1016/j.ynstr.2020.100269. eCollection 2020 Nov.
Childhood adversity increases vulnerability to alcohol use disorders and preclinical models are needed to investigate the underlying neurobiological mechanisms. The present study modeled early-life adversity by rearing male and female C57BL/6J mouse pups in a limited bedding and nesting (LBN) environment, which induces erratic maternal care. As adults, mice were given limited access to two-bottle choice (2BC) alcohol drinking, combined or not with chronic intermittent ethanol (CIE) vapor inhalation to induce alcohol dependence. We tested the hypothesis that LBN rearing might exacerbate or facilitate the emergence of the motivational and affective effects of CIE. Consistent with our hypothesis, although LBN-reared males consumed the same baseline levels of alcohol as controls, they escalated their ethanol intake at an earlier stage of CIE exposure, i.e., after 4 rounds vs. 5 rounds for controls. In contrast, females were insensitive to both LBN rearing and CIE exposure. Males were further subjected to a behavioral test battery. Withdrawal from CIE-2BC increased digging activity and lowered mechanical nociceptive thresholds regardless of early-life conditions. On the other hand, LBN-reared CIE-2BC males showed reduced open arm exploration in the elevated plus maze and increased immobility in the tail suspension test compared to alcohol-naïve counterparts, while no group differences were detected among control-reared males. Finally, LBN rearing and alcohol exposure did not affect grooming in response to a sucrose spray (splash test), novel object recognition, or corticosterone levels. In summary, the LBN experience accelerates the transition from moderate to excessive alcohol drinking and produces additional indices of affective dysfunction during alcohol withdrawal in C57BL/6J male mice.
童年期逆境会增加患酒精使用障碍的易感性，因此需要临床前模型来研究潜在的神经生物学机制。本研究通过在有限垫料和筑巢（LBN）环境中饲养雄性和雌性C57BL/6J幼鼠来模拟早期生活逆境，这种环境会导致母性照顾不稳定。成年后，给予小鼠有限的两瓶选择（2BC）酒精饮料，同时或不同时结合慢性间歇性乙醇（CIE）蒸汽吸入以诱导酒精依赖。我们检验了这样一个假设，即LBN饲养可能会加剧或促进CIE的动机和情感效应的出现。与我们的假设一致，尽管LBN饲养的雄性小鼠摄入的酒精基线水平与对照组相同，但它们在CIE暴露的早期阶段（即4轮后，而对照组为5轮后）就增加了乙醇摄入量。相比之下，雌性小鼠对LBN饲养和CIE暴露均不敏感。对雄性小鼠进一步进行了一系列行为测试。无论早期生活条件如何，从CIE-2BC戒断都会增加挖掘活动并降低机械性伤害感受阈值。另一方面，与未接触酒精的雄性小鼠相比，LBN饲养的CIE-2BC雄性小鼠在高架十字迷宫中的开放臂探索减少，在悬尾试验中的不动时间增加，而在对照饲养的雄性小鼠中未检测到组间差异。最后，LBN饲养和酒精暴露对蔗糖喷雾（泼溅试验）引起的梳理行为、新物体识别或皮质酮水平没有影响。总之，LBN经历加速了C57BL/6J雄性小鼠从适度饮酒到过度饮酒的转变，并在酒精戒断期间产生了情感功能障碍的额外指标。
