Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Genes Brain Behav. 2023 Apr;22(2):e12844. doi: 10.1111/gbb.12844. Epub 2023 Feb 13.
Nicotine is the reinforcing ingredient in tobacco. Following chronic exposure, sudden cessation of nicotine use produces negative symptoms of withdrawal that contribute to dependence. The molecular mechanisms underlying nicotine withdrawal behaviors, however, are poorly understood. Using recombinant inbred mice, chronic nicotine was delivered by minipump and withdrawal induced using mecamylamine. Somatic signs of withdrawal, and anxiety-like behavior using elevated plus maze, were then assessed. Interval mapping was used to identify associations between genetic variation and withdrawal behaviors, and with basal gene expression. Differential gene expression following nicotine exposure and withdrawal was also assessed in progenitor mice using microarrays. Quantitative trait loci mapping identified chromosome intervals with significant genetic associations to somatic signs of withdrawal or withdrawal-induced anxiety-like behavior. Using bioinformatics, and association with basal gene expression in nucleus accumbens, we implicated Rb1, Bnip3l, Pnma2, Itm2b, and Kif13b as candidate genes for somatic signs of withdrawal, and Galr1, which showed trans-regulation from a region of chromosome 14 that was associated with somatic signs of withdrawal. Candidate genes within the chromosome 9 region associated with anxiety-like withdrawal behavior included Dixdc1, Ncam1, and Sorl1. Bioinformatics identified six genes that were also significantly associated with nicotine or alcohol traits in recent human genome-wide association studies. Withdrawal-associated somatic signs and anxiety-like behavior had strong non-overlapping genetic associations, respectively, with regions of chromosome 14 and chromosome 9. Genetic, behavioral and gene expression correlations, and bioinformatics analysis identified several candidate genes that may represent novel molecular targets for modulating nicotine withdrawal symptoms.
尼古丁是烟草中的强化成分。长期接触后，突然停止使用尼古丁会产生戒断的负面症状，导致依赖。然而，尼古丁戒断行为的分子机制仍不清楚。使用重组近交系小鼠，通过微量泵给予慢性尼古丁，并使用美加仑胺诱导戒断。然后评估戒断的躯体症状和高架十字迷宫中的焦虑样行为。间隔映射用于识别遗传变异与戒断行为之间的关联，并与基础基因表达相关联。使用微阵列评估尼古丁暴露和戒断后祖细胞中的差异基因表达。数量性状基因座映射确定了与躯体戒断症状或戒断诱导的焦虑样行为具有显著遗传关联的染色体区间。使用生物信息学，并与伏隔核中的基础基因表达相关联，我们将 Rb1、Bnip3l、Pnma2、Itm2b 和 Kif13b 作为躯体戒断症状的候选基因，Galr1 显示出与躯体戒断症状相关的染色体 14 区域的转录调控。与焦虑样戒断行为相关的染色体 9 区域的候选基因包括 Dixdc1、Ncam1 和 Sorl1。生物信息学鉴定出的六个基因也与最近的人类全基因组关联研究中的尼古丁或酒精特征具有显著关联。戒断相关的躯体症状和焦虑样行为分别与染色体 14 和染色体 9 的区域具有强烈的非重叠遗传关联。遗传、行为和基因表达相关性以及生物信息学分析确定了几个候选基因，它们可能代表调节尼古丁戒断症状的新的分子靶点。
