Interactions between prenatal stress and genetics in cocaine responsiveness.

描述（由申请人提供）：可卡因成瘾是一种由遗传和环境因素相互作用导致的复杂表型。这一建议的总体基本原理是，特定的多基因背景与特定的经历相互作用，决定了可卡因的反应性，使个体或多或少容易上瘾。我们的目标是阐明调节早期环境经历改变成人对可卡因反应能力的遗传因素。广泛的研究集中在描述特定的早期（以及成人）环境条件，增加可卡因的反应。流行病学数据表明，在自然灾害和人为灾害期间，子宫内胎儿的神经精神疾病普遍增加。在动物研究中，产前压力产生成人表型，包括对可卡因的精神运动刺激作用增加敏感性，在可卡因自我服用期间增加可卡因摄入量，以及在灭绝和恢复过程中增加可卡因寻求，这表明早期生活压力的历史更容易产生可卡因成瘾。相反，广泛的研究也集中在确定哪些基因变异会增加可卡因的反应。临床和家族性研究表明，可卡因成瘾有很大的遗传性，最小的估计表明，遗传变异可以解释个体成瘾易感性变异的30%。在动物实验中，已观察到不同小鼠品系在可卡因的行为和生理影响方面存在实质性差异。此外，小鼠基因组的绘制以及重组近交小鼠品系面板的构建，现在可以定量分析特定基因位点对可卡因反应的贡献。相反，有新的证据表明基因-环境相互作用决定了可卡因的反应性，目前，我们预测个体可卡因反应性的一个主要障碍是缺乏对基因和环境之间相互作用的系统调查，而这些因素的确定将有助于先验地确定有可卡因成瘾风险的个体。因此，现在是时候通过结合基因-环境相互作用的系统调查来扩展数量性状基因座分析，例如确定促进或阻碍可卡因反应的早期环境调节的特定遗传基因座。本研究的总体目标是利用小鼠模型分析成瘾易感性遗传易感性的早期环境调节。目的1将评估产前应激（PNS）诱导的两种小鼠品系（C57BL/6和DABA/2J）及其F1后代之间可卡因反应性的差异。这将包括评估毒株x PNS在剂量-反应曲线上的变化，不仅是精神兴奋剂，还包括可卡因的奖励特性，以及对轻度心理和生理压力源的反应，以及这些反应中反复暴露的神经适应性。为了更直接地研究特定遗传因素（在染色体位点水平）与早期环境胁迫之间的相互作用，Aim 2将研究PNS对源自C57BL/6和DBA/2亲本系的重组自交系可卡因反应性的影响，然后进行数量性状位点（QTL）分析，以确定哪些特定染色体位点与PNS诱导的可卡因反应性变化有关。此外，这些反应的对照数据将用于重复和扩展以前的RI-QTL研究。最后，将对遗传和表型变量进行多变量分析，以确定这些变量之间的相互关系，试图确定控制可卡因反应的聚类因素。这些研究将通过确定pns诱导的可卡因反应性变化的特定遗传介质，为基因-环境相互作用提供新的分析。

DESCRIPTION (provided by applicant): Cocaine addiction is a complex phenotype resulting from an interaction from genetic and environmental factors. The overall-arching rationale for this proposal is that specific polygenetic backgrounds interact with specific experiences to determine cocaine responsiveness making an individual more or less vulnerable to cocaine addiction. Our goal is to elucidate genetic factors that modulate the ability of early environmental experiences to alter adult responsiveness to cocaine. Extensive research has focused on delineating specific early (as well as adult) environmental conditions that increase cocaine responsiveness. Epidemiological data indicates broad-spectrum increases in neuropsychiatric disease for that are in utero during natural and man- made disaster. In animal studies, prenatal stress produces an adult phenotype comprising increased sensitivity to psychomotor stimulant effects of cocaine, greater cocaine intake during cocaine self-administration, and higher cocaine-seeking during extinction and reinstatement procedures suggesting that a history of early life stress produce greater vulnerability to cocaine addiction. Conversely, extensive research has also focused on determining which gene variants increase cocaine responsiveness. Clinical and familial studies indicate a substantial inheritance to cocaine addiction with minimal estimates indicating genetic variability can account for 30% of variability in addiction vulnerability across individuals. In animal studies, substantial differences between mouse strains have been observed in the behavioral and physiological effects of cocaine. Further, the mapping of the mouse genome along with the construction recombinant inbred mouse strain panels now allows quantitative analyses of the contribution of specific genetic loci to cocaine responsiveness. Conversely there is emerging evidence for gene-environment interactions in determining cocaine responsiveness, and, currently, a major impediment to our ability to predict individual cocaine responsiveness is the lack of systematic investigation of the interactions between genes and environment and determination of these factors will facilitate a priori determination of individuals at risk for cocaine addiction. Thus, it is now time to extend quantitative trait loci analyses by incorporating systematic investigation of gene-environment interactions, for e.g. determination of the specific genetic loci genes that facilitate or impede early environmental modulation of cocaine responsiveness. The overall goal of the present proposal is to provide an analysis of the early environmental modulation of genetic predisposition to addiction vulnerability employing a mouse model. Aim 1 will assess prenatal stress (PNS)-induced differences in cocaine responsiveness between two mouse strains that show distinct cocaine responsiveness (C57BL/6 and DABA/2J) and their F1 progeny. This will include assessment of strain x PNS shifts in the dose-response curve for not only the psychostimulant, but also the rewarding, properties of cocaine as well as responsiveness to mild psychological and physical stressors and neuroadaptations in these responses with repeated exposures. In order to more directly investigate the interaction between specific genetic factors (at the chromosomal loci level) and early environmental stress, Aim 2 will examine the impact of PNS on cocaine responsiveness in across a panel of recombinant inbred strains derived from C57BL/6 and DBA/2 parental lines followed by quantitative trait loci (QTL) analyses to allow determination which specific chromosomal loci are associated with PNS-induced changes in cocaine responsiveness. In addition, control data for these responses will be utilized to replicate and extend previous RI-QTL studies. Finally, multivariant analyses will be performed on the genetic and phenotypic variables in order to determine inter-relatedness of these variables in attempt to define cluster factors that control cocaine responsiveness. These studies will provide novel analyses of gene-environment interactions by determining the specific genetic mediators of PNS-induced changes in cocaine responsiveness. PUBLIC HEALTH RELEVANCE: There are marked individual differences in vulnerability to drug addiction which result from complex genetic and environmental interactions, however, there is limited research examining such interactions. The proposed research will examine the interaction between two model systems that examine the contribution of genetic variation (recombinant inbred mouse lines) and the contribution of adverse early environmental conditions (prenatal stress). The goal of this project is to identify genetic factors, at the level of specific chromosomal loci, that predispose individuals to the dramatic developmental changes produced by early stress resulting in high addiction vulnerability and these findings will set the foundation for a detailed understanding of the intricate interactions between genome and environment in determination of this phenotype.