Yao Hui, Wang Changliang, Xia Zhixiu
Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China; Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, P. R. China.
The People's Procuratorate of Liaoning Province Judicial Authentication Center, No. 46, Cong San East Road, Shenyang, Liaoning 110032, PR China.
J Affect Disord. 2023 Mar 1;324:143-152. doi: 10.1016/j.jad.2022.12.069. Epub 2022 Dec 29.
Prenatal alcohol exposure (PAE) adversely affects the neurobiological and behavioral functions of offspring. Increasing evidence indicates that alcohol-use disorders and post-traumatic stress disorder (PTSD) commonly co-occur. Enhanced function of hyperpolarization-activated gated channel 1 (HCN1) may be involved in the pathogenesis of PTSD. This study aimed to explore the effect of PAE on fear extinction, spontaneous recovery, alcohol preference, and function of HCN1 channels in offspring of both sexes.
The PAE model was established with a 20 % (m/V) ethanol solution, and offspring were treated with 0.5, 1, and 2 μg/mL ZD7288 to block the HCN1 channel. Behavioral tests were used to detect the mental state and fear of extinction of the mice. Western blot was used to detect HCN1 expression in the synaptosomes. The BDNF/TrkB-pmTOR pathway was also examined.
ZD7288 administration ameliorated PAE-induced impairment of fear extinction and depression-like behavior. ZD7288 administration also alleviated PAE-induced inhibition of the HCN1 channel in the prefrontal cortex (PFC) and the BDNF/TrkB-pmTOR pathway in the hippocampus of offspring. In addition, the therapeutic effect of ZD7288 in males was better than that in females.
Overall, these results suggest that PAE enhances alcohol preference and susceptibility to PTSD through synaptic HCN1 channels in the PFC. In addition, ZD7288 may be a promising candidate for preventing alcohol-associated PTSD-like syndrome, particularly in males.
The effects of ZD7288 were only studied in PAE animals and not in healthy animals.
孕期酒精暴露（PAE）会对后代的神经生物学和行为功能产生不利影响。越来越多的证据表明，酒精使用障碍和创伤后应激障碍（PTSD）常常同时出现。超极化激活的门控通道1（HCN1）功能增强可能参与了PTSD的发病机制。本研究旨在探讨PAE对两性后代恐惧消退、自发恢复、酒精偏好及HCN1通道功能的影响。
用20%（m/V）乙醇溶液建立PAE模型，并用0.5、1和2μg/mL的ZD7288处理后代以阻断HCN1通道。采用行为测试来检测小鼠的精神状态和恐惧消退情况。用蛋白质免疫印迹法检测突触体中HCN1的表达。同时也检测了BDNF/TrkB-pmTOR通路。
给予ZD7288可改善PAE诱导的恐惧消退障碍和抑郁样行为。给予ZD7288还可减轻PAE诱导的后代前额叶皮质（PFC）中HCN1通道抑制以及海马中BDNF/TrkB-pmTOR通路的抑制。此外，ZD7288对雄性的治疗效果优于雌性。
总体而言，这些结果表明，PAE通过PFC中的突触HCN1通道增强酒精偏好和对PTSD的易感性。此外，ZD7288可能是预防酒精相关PTSD样综合征的有前景的候选药物，尤其是对男性。
ZD7288的作用仅在PAE动物中进行了研究，未在健康动物中研究。
