纯合敲除小鼠表现出增强的乙醇条件性位置偏爱和急性乙醇诱导的抗焦虑行为。

Homozygous Knockout Mice Exhibit Increased Ethanol Conditioned Place Preference and Acute Ethanol-Induced Anxiolytic Behavior.

作者信息

Hernández Maribel, Barkley-Levenson Amanda M

机构信息

Deparment of Pharmaceutical Sciences - University of New Mexico Health Sciences Center Albuquerque, NM 87131, USA.

出版信息

bioRxiv. 2025 Aug 18:2025.08.15.670589. doi: 10.1101/2025.08.15.670589.

Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96bf/12393419/1cbf2e231fe0/nihpp-2025.08.15.670589v1-f0001.jpg

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