Discovery of early life stress interacting and sex-specific quantitative trait loci impacting cocaine responsiveness
Discovery of early life stress interacting and sex-specific quantitative trait loci impacting cocaine responsiveness
复制标题
DOI：
10.1111/bph.14661
复制
发表时间：
2019-11-01
影响因子：
7.3
通讯作者：
Kippin, Tod E.
中科院分区：
文献类型：
--
作者：
Bagley, Jared R.;Szumlinski, Karen K.;Kippin, Tod E.
背景和目的成瘾易感性涉及复杂的基因X环境相互作用，导致对药物的病理反应。识别参与这些相互作用的基因是理解潜在神经生物学的重要一步，很少有这样的分析检查性别特异性的影响。为了剖析这种相互作用，我们研究了产前应激（PNS）对BXD重组近交系小鼠的雄性和雌性可卡因反应性的影响。实验方法BXD菌株进行定时交配，并分配到PNS或对照组。从胚胎第11天至第14天（E）开始，对PNS母体进行束缚应激（1小时束缚，每日三次），并持续至分娩。成年男性和女性，控制和PNS后代进行了测试的运动反应的初始和重复可卡因注射（致敏），以及可卡因诱导的条件性位置偏好（CPP）。应变，PNS和性别相互作用，以调节初始和致敏可卡因诱导的运动，以及CPP。此外，数量性状位点（QTL）与PNS相互作用调节初始运动反应可卡因（X染色体，37.91至50.95 Mb）被确定。还鉴定了调节CPP（11号染色体，65.50至81.31 Mb）和致敏可卡因诱导的运动（16号染色体，95.79至98.32 Mb）的不依赖于PNS的雌性特异性QTL。利用公开的mRNA表达数据来鉴定顺式eQTL和转录物与行为表型的共变异，以优先考虑候选基因，包括Aifm1。结论和影响这些QTL包括基因，可能温和的遗传易感性PNS和性别相互作用，以确定成人可卡因和成瘾的脆弱性。链接文章这篇文章是关于药理学研究中性别差异的重要性的主题部分的一部分。要查看本节中的其他文章，请访问
Background and Purpose Addiction vulnerability involves complex gene X environment interactions leading to a pathological response to drugs. Identification of the genes involved in these interactions is an important step in understanding the underlying neurobiology and rarely have such analyses examined sex-specific influences. To dissect this interaction, we examined the impact of prenatal stress (PNS) on cocaine responsiveness in male and female mice of the BXD recombinant inbred panel. Experimental Approach BXD strains were subjected to timed mating and assigned to PNS or control groups. PNS dams were subjected to restraint stress (1-hr restraint, three times daily) starting between embryonic day (E) 11 and 14 and continued until parturition. Adult male and female, control and PNS offspring were tested for locomotor response to initial and repeated cocaine injections (sensitization) as well as cocaine-induced conditioned place preference (CPP). Key Results Strain, PNS, and sex interacted to modulate initial and sensitized cocaine-induced locomotion, as well as CPP. Moreover, a quantitative trait locus (QTL) interacting with PNS regulating initial locomotor response to cocaine (chromosome X, 37.91 to 50.95 Mb) was identified. Also PNS-independent, female-specific QTLs regulating CPP (chromosome 11, 65.50 to 81.31 Mb) and sensitized cocaine-induced locomotion (chromosome 16, 95.79 to 98.32 Mb) were identified. Publicly available mRNA expression data were utilized to identify cis-eQTL and transcript covariation with the behavioural phenotype to prioritize candidate genes; including Aifm1. Conclusions and Implications These QTL encompass genes that may moderate genetic susceptibility to PNS and interact with sex to determine adult responsiveness to cocaine and addiction vulnerability. LINKED ARTICLES This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit