Pharmacology Graduate Group, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Neuropharmacology. 2022 Sep 15;216:109170. doi: 10.1016/j.neuropharm.2022.109170. Epub 2022 Jun 22.
Alcohol and nicotine are commonly used during adolescence, establishing long-lasting neuroplastic alterations that influence subsequent drug use and abuse. Drinking- and smoking-related traits have been extensively associated with variation in CHRNA5 - the gene that encodes the α5 subunit of neuronal nicotinic acetylcholine receptors (nAChRs). The single nucleotide polymorphism (SNP) rs16969968 in CHRNA5 encodes an amino acid substitution (D398N) that alters the function and pharmacokinetics of α5-containing nAChR. When expressed in rodents, this variant results in increased ethanol and nicotine operant self-administration. How disruption of α5-containing nAChRs influences adolescent ethanol and nicotine intake, and how it modulates interactions between these drugs has not been previously explored. In the present study, we examined volitional ethanol and nicotine consumption in adolescent mice (post-natal day 30-43) of both sexes with mutated (SNP) or lacking (KO) the α5 nAChR subunit. The effect of adolescent alcohol or nicotine exposure on home cage consumption of the opposite drug in adulthood and its modulation by Chrna5 mutation and sex were examined. During adolescence, we found that α5 nAChR disruption increases nicotine intake in mice of both sexes, but the effect on alcohol intake was only observed in females. The sex-specific increase in alcohol consumption in α5 SNP and KO was replicated in adulthood. The effect of adolescent alcohol or nicotine exposure on subsequent intake of the opposite drug in adulthood is modulated by sex and Chrna5 mutation. These observations suggest sex differences in the genetic architecture of alcohol dependence, and modulators of alcohol and nicotine interactions.
酒精和尼古丁在青少年中普遍使用，会造成持久的神经可塑性改变，从而影响随后的药物使用和滥用。与饮酒和吸烟相关的特征与 CHRNA5 基因的变异密切相关，该基因编码神经元烟碱型乙酰胆碱受体 (nAChR) 的α5 亚单位。CHRNA5 中的单核苷酸多态性 (SNP) rs16969968 编码一个氨基酸替换 (D398N)，改变了含有α5 的 nAChR 的功能和药代动力学。当在啮齿动物中表达时，这种变体导致乙醇和尼古丁操作性自我给药增加。破坏含有α5 的 nAChR 如何影响青少年时期的乙醇和尼古丁摄入，以及它如何调节这些药物之间的相互作用，以前尚未探索过。在本研究中，我们研究了具有突变（SNP）或缺乏（KO）α5 nAChR 亚单位的雄性和雌性青少年小鼠（出生后第 30-43 天）的自愿性乙醇和尼古丁消耗。检查了青春期酒精或尼古丁暴露对成年期相反药物的笼内消耗的影响，以及 Chrna5 突变和性别对其的调节作用。在青春期，我们发现α5 nAChR 破坏会增加雌雄小鼠的尼古丁摄入量，但对酒精摄入量的影响仅在雌性中观察到。在α5 SNP 和 KO 中观察到的酒精消耗的性别特异性增加在成年期得到了复制。青春期酒精或尼古丁暴露对成年期相反药物随后摄入的影响受性别和 Chrna5 突变的调节。这些观察结果表明，酒精依赖的遗传结构存在性别差异，以及酒精和尼古丁相互作用的调节剂。
