Interactions between prenatal stress and genetics in cocaine responsiveness.

描述(申请人提供)：可卡因成瘾是一种复杂的表型，是遗传和环境因素相互作用的结果。这一提议的总体基本理由是，特定的多基因背景与特定的经验相互作用，以确定可卡因的反应性，使个人或多或少容易受到可卡因成瘾的影响。我们的目标是阐明调节早期环境经验能力的遗传因素，以改变成年人对可卡因的反应。广泛的研究侧重于描述增加可卡因反应性的特定早期(以及成年)环境条件。流行病学数据表明，在自然和人为灾难期间在子宫内的神经精神疾病广泛增加。在动物研究中，产前应激产生一种成年表型，包括对可卡因的精神运动刺激效应的敏感度增加，自我给药期间可卡因摄入量增加，以及在灭绝和恢复过程中寻求可卡因的次数增加，这表明早期生活应激史导致对可卡因成瘾的更大易感性。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性。临床和家族学研究表明，可卡因成瘾有很大的遗传，最低限度的估计表明，遗传变异性可以解释个体成瘾易感性的30%的变异性。在动物研究中，已经观察到不同品系的小鼠在可卡因的行为和生理效应上存在显著差异。此外，随着小鼠基因组图谱的绘制以及重组近交系小鼠品系面板的构建，现在可以定量分析特定遗传位点对可卡因反应的贡献。相反，在确定可卡因反应性方面，有新的证据表明基因-环境相互作用，目前，我们预测个人可卡因反应性的能力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，而确定这些因素将有助于事先确定有可卡因成瘾风险的个人。因此，现在是时候通过纳入对基因-环境相互作用的系统研究来扩展数量性状基因座分析，例如确定促进或阻碍早期环境调节可卡因反应的特定遗传基因座。本提案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评估产前应激(PNS)诱导的两个可卡因反应性不同的小鼠品系(C57BL/6和Daba/2J)及其F1后代之间的可卡因反应性差异。这将包括评估菌株x PNS在剂量-反应曲线上的变化，不仅包括精神刺激剂，而且还包括可卡因的回报、特性以及对轻微心理和身体应激源的反应，以及反复暴露这些反应中的神经适应。为了更直接地研究特定遗传因素(在染色体基因水平)与早期环境应激之间的相互作用，Aim 2将研究三七总皂苷对来自C57BL/6和DBA/2亲本的重组近交系可卡因反应的影响，然后进行数量性状基因座(QTL)分析，以确定哪些特定染色体基因座与三七总皂苷诱导的可卡因反应变化有关。此外，这些响应的对照数据将被用于复制和扩展先前的RI-QTL研究。最后，将对遗传和表型变量进行多变量分析，以确定这些变量的相互关联性，试图确定控制可卡因反应的集群因素。这些研究将通过确定三七总皂苷诱导的可卡因反应性变化的特定遗传媒介，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.