Department of Biobehavioral Health, Penn State University, University Park, PA, USA.
The Huck Institutes for the Life Sciences, Penn State University, University Park, PA, USA.
Neuropharmacology. 2022 Dec 15;221:109279. doi: 10.1016/j.neuropharm.2022.109279. Epub 2022 Oct 5.
Genetic background impacts sensitivity to nicotine's rewarding and aversive effects and metabolism, which influences susceptibility to nicotine addiction. This is important because sensitivity to nicotine influences susceptibility to nicotine addiction. Thus, understanding genetic contribution to nicotine sensitivity can aid in identifying risk factors for nicotine addiction. Genetic variability in addiction phenotypes can be modeled in rodent systems, and comparisons of nicotine sensitivity in inbred mice can identify contributing genetic substrates. Our laboratory has identified differences in nicotine sensitivity in male mice from two inbred mouse strains, C57BL/6J and NOD/ShiLtJ. We found that the NOD/ShiLtJ strain experienced greater nicotine-induced locomotor depression and hypothermia than the C57BL/6J strain. To investigate possible differences in nicotine metabolism between strains, subjects were treated with acute nicotine and serum and urine samples were analyzed using LC-MS/MS to quantify nicotine and metabolites. This analysis revealed that NOD/ShiLtJ mice had similar serum nicotine but lower cotinine and 3'-hydroxycotinine levels after nicotine treatment when compared to C57BL/6J mice. Possible genetic factors mediating strain differences were identified by surveying nicotine sensitivity- and metabolism-related genes within the Mouse Phenome Database SNP retrieval tool. Polymorphisms were found in 15 of the 26 examined gene sequences. Liver expression levels of nicotine metabolism-related genes (Cyp2a5, Cyp2a4, and Aox1) were measured using qPCR. NOD/ShiLtJ mice showed lower expression of Cyp2a5 and Cyp2a4 and greater expression of Aox1 in liver tissue. These data demonstrate complex differences in nicotine sensitivity and metabolism driven by genetic differences between C57BL/6J and NOD/ShiLtJ inbred mouse strains.
遗传背景会影响对尼古丁奖赏和厌恶效应以及代谢的敏感性，从而影响对尼古丁成瘾的易感性。这一点很重要，因为对尼古丁的敏感性会影响对尼古丁成瘾的易感性。因此，了解遗传因素对尼古丁敏感性的影响有助于确定尼古丁成瘾的风险因素。成瘾表型的遗传变异性可以在啮齿动物系统中建模，并且比较近交系小鼠对尼古丁的敏感性可以确定遗传基础。我们的实验室已经发现了两种近交系小鼠（C57BL/6J 和 NOD/ShiLtJ）中雄性小鼠对尼古丁敏感性的差异。我们发现 NOD/ShiLtJ 品系比 C57BL/6J 品系经历了更大的尼古丁引起的运动抑制和体温降低。为了研究两种品系之间尼古丁代谢可能存在的差异，用 LC-MS/MS 对急性尼古丁处理后的血清和尿液样本进行分析，以定量尼古丁和代谢物。该分析表明，与 C57BL/6J 小鼠相比，NOD/ShiLtJ 小鼠在接受尼古丁处理后具有相似的血清尼古丁水平，但更低的可替宁和 3'-羟基可替宁水平。通过在 Mouse Phenome Database SNP 检索工具中调查与尼古丁敏感性和代谢相关的基因，鉴定出可能介导品系差异的遗传因素。在 26 个被检查的基因序列中发现了 15 个多态性。使用 qPCR 测量了与尼古丁代谢相关的基因（Cyp2a5、Cyp2a4 和 Aox1）在肝脏中的表达水平。NOD/ShiLtJ 小鼠肝脏组织中 Cyp2a5 和 Cyp2a4 的表达水平较低，Aox1 的表达水平较高。这些数据表明，C57BL/6J 和 NOD/ShiLtJ 近交系小鼠之间的遗传差异导致了尼古丁敏感性和代谢的复杂差异。
