School of Psychology, Victoria University of Wellington, PO Box 600, 6104, Wellington, New Zealand.
Department of Population Health Sciences, University of Utrecht, Yalelaan 2, 3584 CM, Utrecht, the Netherlands.
Psychopharmacology (Berl). 2022 Oct;239(10):3145-3159. doi: 10.1007/s00213-022-06195-5. Epub 2022 Aug 8.
Alcohol use disorder (AUD) is shown to have an overall heritability of around 50%. One of the genes associated with AUD is SLC6A4 (solute carrier family 6 member A4) which codes for the serotonin transporter (SERT). The study looked at serotonin dysfunction on ethanol consumption in adolescents and the subsequent intergenerational effects of drinking by using a rat model: SERT (regular functioning), SERT (50% transporter reduction) and SERT (complete reduction).
We investigated sex and genotype differences in ethanol consumption in SERT knock-out Wistar rats (F0) followed by studying behaviour in the offspring (F1) of the male drinkers to assess effects of paternal alcohol consumption.
An intermittent access two-bottle choice paradigm (IA2BC) was used to yield ethanol drinking behaviour in F0 adolescent Wistar rats. The highest drinking males were mated to alcohol-naive females and their offspring were compared with controls. Drinking behaviour (IA2BC) and ethanol-induced motor coordination effects (via rotarod) were measured in the F1s.
F0 drinking saw no SERT genotype differences in males. However, females consumed higher volumes of ethanol compared to males, with SERT females showing the highest intake. A clearer genotype effect was seen in the F1 animals, with reduction in SERT activity leading to enhanced ethanol intake in both sexes. Importantly, paternal exposure to ethanol significantly reduced the ethanol induced motor side effects in offspring, independent of sex and genotype.
These indicate a difference in the way genetic factors may act across sexes and suggest the involvement of epigenetic mechanisms in the intergenerational effects of alcohol.
酒精使用障碍（AUD）的整体遗传率约为 50%。与 AUD 相关的基因之一是 SLC6A4（溶质载体家族 6 成员 A4），它编码 5-羟色胺转运体（SERT）。该研究使用大鼠模型研究了青少年时期乙醇消耗中 5-羟色胺功能障碍以及随后的代际饮酒效应：SERT（正常功能）、SERT（转运体减少 50%）和 SERT（完全减少）。
我们研究了 SERT 敲除 Wistar 大鼠（F0）中乙醇消耗的性别和基因型差异，然后研究了雄性饮酒者后代（F1）的行为，以评估父代饮酒的影响。
使用间歇性访问双瓶选择范式（IA2BC）来获得 F0 青少年 Wistar 大鼠的乙醇饮用行为。最高饮酒的雄性与酒精-naive 雌性交配，比较其后代与对照组。在 F1 中测量饮酒行为（IA2BC）和乙醇诱导的运动协调效应（通过转棒）。
F0 饮酒中 SERT 基因型在雄性中没有差异。然而，雌性比雄性消耗更多的乙醇，SERT 雌性的摄入量最高。在 F1 动物中观察到更明显的基因型效应，SERT 活性降低导致两性乙醇摄入量增加。重要的是，父代暴露于乙醇显著降低了后代的乙醇诱导的运动副作用，与性别和基因型无关。
这表明遗传因素在两性中的作用方式存在差异，并表明酒精的代际效应涉及表观遗传机制。
