Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
Murcia Research Institute of Health Sciences (IMIB), Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain.
Prog Neuropsychopharmacol Biol Psychiatry. 2021 Jan 10;104:110025. doi: 10.1016/j.pnpbp.2020.110025. Epub 2020 Jun 27.
Alcohol interferes with foetal development and prenatal alcohol exposure can lead to adverse effects known as foetal alcohol spectrum disorders. We aimed to assess the underlying neurobiological mechanisms involved in alcohol intake and withdrawal in adolescent mice exposed to alcohol during early life stages, in discrete brain areas. Pregnant C57BL/6 female mice were exposed to binge alcohol drinking from gestation to weaning. Subsequently, alcohol seeking and taking behaviour were evaluated in male adolescent offspring, as assessed in the two-bottle choice and oral self-administration paradigms. Brain area samples were analysed to quantify AMPAR subunits GluR1/2 and pCREB/CREB expression following alcohol self-administration. We measured the expression of mu and kappa opioid receptors both during acute alcohol withdrawal (assessing anxiety alterations by the EPM test) and following reinstatement in the two-bottle choice paradigm. In addition, alcohol metabolism was analysed by measuring blood alcohol concentrations under an acute dose of 3 g/kg alcohol. Our findings demonstrate that developmental alcohol exposure enhances alcohol intake during adolescence, which is associated with a decrease in the pCREB/CREB ratio in the hippocampus, prefrontal cortex and striatum, while the GluR1/GluR2 ratio showed a decrease in the hippocampus. Moreover, PLAE mice showed behavioural alterations, such as increased anxiety-like responses during acute alcohol withdrawal, and higher BAC levels. No significant changes were identified for mu and kappa opioid receptors mRNA expression. The current study highlights that early alcohol exposed mice increased alcohol consumption during late adolescence. Furthermore, a diminished CREB signalling and glutamatergic neuroplasticity are proposed as underpinning neurobiological mechanisms involved in the sensitivity to alcohol reinforcing properties.
酒精会干扰胎儿发育，产前酒精暴露可导致胎儿酒精谱系障碍等不良后果。我们旨在评估在生命早期阶段暴露于酒精的青春期小鼠中，在不同脑区中与酒精摄入和戒断相关的潜在神经生物学机制。怀孕的 C57BL/6 雌性小鼠从妊娠到断奶期间接受 binge 酒精灌胃。随后，在双瓶选择和口服自我给药范式中评估雄性青春期后代的酒精寻求和摄取行为。在酒精自我给药后，分析脑区样本以定量 AMPAR 亚基 GluR1/2 和 pCREB/CREB 的表达。我们在急性酒精戒断期间（通过 EPM 测试评估焦虑改变）和双瓶选择范式中的再巩固后，测量了 mu 和 kappa 阿片受体的表达。此外，通过测量 3g/kg 酒精急性剂量下的血液酒精浓度来分析酒精代谢。我们的研究结果表明，发育性酒精暴露会增强青春期的酒精摄入，这与海马体、前额叶皮层和纹状体中的 pCREB/CREB 比值降低有关，而海马体中的 GluR1/GluR2 比值降低。此外，PLAE 小鼠表现出行为改变，例如在急性酒精戒断期间焦虑样反应增加和 BAC 水平升高。未发现 mu 和 kappa 阿片受体 mRNA 表达的显著变化。本研究强调了早期酒精暴露的小鼠在青春期晚期增加了酒精摄入。此外，CREB 信号转导和谷氨酸能神经可塑性的减弱被提出作为参与对酒精强化特性敏感性的潜在神经生物学机制。
