Hernández Maribel, Barkley-Levenson Amanda M
Deparment of Pharmaceutical Sciences - University of New Mexico Health Sciences Center Albuquerque, NM 87131, USA.
bioRxiv. 2025 Aug 18:2025.08.15.670589. doi: 10.1101/2025.08.15.670589.
The gene has been associated with behavioral phenotypes of alcohol use disorder (AUD) in recent human genome wide association studies. To further assess the role of this gene in ethanol-related traits, we tested knockout (KO) mice for ethanol conditioned place preference (CPP), locomotor activity, and ethanol-induced anxiolysis. Male homozygous KO mice (HOM) showed greater preference for the ethanol-paired context compared to wild type littermates (WT) and heterozygous KO mice (HET), while female mice showed no genotypic difference. HOM of both sexes exhibited greater novelty-induced hyperactivity in the CPP apparatus than HET and WT mice in the first two minutes. In a separate experiment, HOM mice showed enhanced locomotor activity following a 1.5 g/kg ethanol injection; however, they also displayed greater locomotor activity during habituation, suggesting basal locomotor differences. Following 1.5 and 2 g/kg injections, HOM mice exhibited EtOH-induced anxiolysis in the first 5 minutes, while the HET and WT mice did not. Lastly, HOM mice displayed a significant sedative response compared to WT animals following a 2 g/kg injection of ethanol. Ultimately, these findings validate a role for in modulating ethanol's rewarding, anxiolytic, and sedative effects in a sex-dependent manner.
在最近的人类全基因组关联研究中，该基因已与酒精使用障碍（AUD）的行为表型相关联。为了进一步评估该基因在乙醇相关性状中的作用，我们对基因敲除（KO）小鼠进行了乙醇条件性位置偏爱（CPP）、运动活性和乙醇诱导的抗焦虑测试。与野生型同窝小鼠（WT）和杂合子基因敲除小鼠（HET）相比，雄性纯合子基因敲除小鼠（HOM）对与乙醇配对的环境表现出更大的偏爱，而雌性小鼠则没有基因型差异。在CPP实验装置中，两性的HOM小鼠在前两分钟比HET和WT小鼠表现出更大的新奇诱导的多动。在另一个实验中，HOM小鼠在注射1.5 g/kg乙醇后表现出增强的运动活性；然而，它们在习惯化过程中也表现出更大的运动活性，表明存在基础运动差异。在注射1.5 g/kg和2 g/kg乙醇后，HOM小鼠在最初5分钟内表现出乙醇诱导的抗焦虑作用，而HET和WT小鼠则没有。最后，与野生型动物相比，HOM小鼠在注射2 g/kg乙醇后表现出显著的镇静反应。最终，这些发现证实了该基因在以性别依赖方式调节乙醇的奖赏、抗焦虑和镇静作用方面的作用。
