Interactions between prenatal stress and genetics in cocaine responsiveness.

产前应激与可卡因反应性遗传之间的相互作用。

• 批准号: 8037211
• 负责人: Tod Edward Kippin
• 金额: $ 32.37万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037211
• 关键词: Accounting; Acute; Adult; Animals; Behavior; Behavioral; Biological Models; Chromosome Mapping; Chromosomes; Clinical; Cocaine; Cocaine Dependence; Code; Complex; DABA; Data; Data Set; Development; Disasters; Disease; Dose; Drug Addiction; Environment; Environmental Risk Factor; Epidemiology; Etiology; Extinction (Psychology); Foundations; Future; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Variation; Genome; Goals; Health; Inbred Mouse; Inbred Strains Mice; Inbreeding; Individual; Individual Differences; Intake; Investigation; Laboratories; Life Experience; Life Stress; Link; Maps; Mediating; Mediator of activation protein; Modeling; Mothers; Mouse Strains; Mus; Nature; Nervous system structure; Phase; Phenotype; Physiological; Pilot Projects; Procedures; Property; Publishing; Quantitative Trait Loci; Rattus; Recombinant Inbred Strain; Recombinants; Recording of previous events; Research; Resolution; Rewards; Risk; Self Administration; Stress; Testing; Time; Training; Travel; Variant; addiction; biological adaptation to stress; design; drug of abuse; experience; gene environment interaction; in utero; indexing; man; mouse genome; mouse model; neuroadaptation; neuropsychiatry; novel; postnatal; pre-clinical; preference; prenatal; prenatal stress; psychologic; psychostimulant; public health relevance; research study; response; stressor; trait

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.

描述（由申请人提供）：可卡因成瘾是一种复杂的表型，由遗传和环境因素的相互作用引起。这一建议的总体理论基础是，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，使一个人或多或少容易对可卡因成瘾。我们的目标是阐明遗传因素，调节能力的早期环境的经验，改变成人可卡因的反应。广泛的研究集中在描绘特定的早期（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，子宫内的神经精神疾病广泛增加。在动物研究中，产前应激产生了一种成人表型，包括对可卡因的精神刺激作用的敏感性增加，可卡因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程度增加，这表明早期生活应激史对可卡因成瘾的脆弱性更大。相反，广泛的研究也集中在确定哪些基因变异增加可卡因的反应性。临床和家族研究表明，可卡因成瘾具有很大的遗传性，最小的估计表明遗传变异性可以占个体成瘾脆弱性变异性的30%。在动物研究中，已经观察到可卡因的行为和生理效应在小鼠品系之间存在实质性差异。此外，小鼠基因组的作图沿着构建重组近交系小鼠品系组现在允许定量分析特定遗传基因座对可卡因反应性的贡献。相反，有新的证据表明，基因与环境的相互作用，在确定可卡因的反应性，目前，我们的能力，以预测个人可卡因的反应性的一个主要障碍是缺乏系统的调查基因和环境之间的相互作用，这些因素的确定将有助于先验确定个人的可卡因成瘾的风险。因此，现在是时候扩展数量性状基因座分析，纳入系统的研究基因环境相互作用，例如确定特定的遗传基因座基因，促进或阻碍早期环境调节可卡因的反应。本提案的总体目标是提供一个分析的早期环境调制的遗传易感性成瘾的脆弱性采用小鼠模型。目的1将评估产前应激（PNS）诱导的可卡因反应性的差异之间的两个小鼠品系，表现出不同的可卡因反应性（C57 BL/6和DABA/2 J）和它们的F1后代。这将包括评估剂量-反应曲线中的应变x PNS变化，不仅是精神兴奋剂，而且还有可卡因的奖励性质，以及对轻度心理和身体应激源的反应性和重复暴露的神经适应性。为了更直接地研究特定遗传因素之间的相互作用（在染色体位点水平）和早期环境压力，目的2将检查PNS对来自C57 BL/6和DBA/2亲本系的重组近交系的组中可卡因响应性的影响，随后进行数量性状基因座（QTL）分析以允许确定哪些特定染色体基因座与PNS相关。引起可卡因反应性的变化。此外，这些响应的对照数据将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，试图定义控制可卡因反应性的聚类因素。这些研究将提供新的分析基因-环境相互作用，通过确定特定的遗传介质的PNS诱导的可卡因反应性的变化。 公共卫生相关性：由于复杂的遗传和环境相互作用，吸毒成瘾的脆弱性存在明显的个体差异，但是，研究这种相互作用的研究有限。拟议的研究将检查两个模型系统之间的相互作用，研究遗传变异（重组近交系小鼠）的贡献和不利的早期环境条件（产前压力）的贡献。该项目的目标是确定遗传因素，在特定的染色体位点的水平上，使个体易于发生由早期压力产生的巨大发育变化，从而导致高度成瘾的脆弱性，这些发现将为详细了解基因组和环境之间的复杂相互作用奠定基础，以确定这种表型。