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）：可卡因成瘾是由遗传和环境因素的相互作用引起的复杂表型。该提案的总体基本原理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能力，从而使个人或多或少容易受到可卡因成瘾。我们的目标是阐明调节早期环境经历改变成人对可卡因的能力的能力的遗传因素。广泛的研究集中在描述提高可卡因反应性的早期（以及成人）环境条件上。流行病学数据表明，在自然和人体造成的灾难中，神经精神疾病的广谱增加。在动物研究中，产前压力会产生一种成人表型，包括对可卡因的心理动物刺激作用的敏感性，可卡因自我给药期间可卡因摄入量的较高以及在灭绝和重新定位过程中寻求更高的可卡因的摄入量，表明早期生活的历史使早期生活的历史更大。相反，广泛的研究还集中在确定哪些基因变异型增加可卡因的反应性。临床和家族研究表明，对可卡因成瘾的实质性遗传和最少的估计值表明遗传变异性可以占个人成瘾脆弱性变异性的30％。在动物研究中，在可卡因的行为和生理作用中已经观察到小鼠菌株之间的实质差异。此外，现在，小鼠基因组以及构造重组近交小鼠应变板的映射可以定量分析特定遗传基因座对可卡因反应性的贡献。相反，在确定可卡因反应性方面存在基因与环境相互作用的新证据，目前，我们预测单个可卡因反应能力的能力的主要障碍是缺乏对基因与环境之间的相互作用的系统研究，并且确定这些因素将促进对可卡因的先验确定可卡因的先验确定。因此，现在是时候通过将基因环境相互作用的系统研究来扩展定量性状基因座分析了，例如确定促进或阻碍可卡因反应性早期环境调节的特定遗传基因座基因。本提案的总体目标是分析使用小鼠模型对成瘾脆弱性的遗传易感性的早期环境调节。 AIM 1将评估两个小鼠菌株之间可卡因反应性的差异，这些小鼠菌株表现出明显的可卡因反应性（C57BL/6和DABA/2J）及其F1后代。这将包括评估X pNS剂量响应曲线中的菌株变化，不仅是心理刺激剂，而且还评估可卡因的奖励性能，以及对轻度心理和身体压力源的响应以及这些反应中对轻度的心理和神经适应的反应。为了更直接地研究特定遗传因素（在染色体基因座水平上）和早期环境压力之间的相互作用，AIM 2将检查PNS对跨C57BL/6和DBA/2的重组近交菌株对可卡因反应性的影响PNS诱导的可卡因反应性变化。此外，这些响应的控制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关性，以定义控制可卡因反应性的群集因子。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体来提供对基因环境相互作用的新分析。 公共卫生相关性：由于复杂的遗传和环境相互作用而导致的药物成瘾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。拟议的研究将研究两个模型系统之间的相互作用，这些模型系统研究了遗传变异的贡献（重组近交小鼠系）和不良早期环境条件（产前应激）的贡献。该项目的目的是在特定的染色体基因座的水平上鉴定遗传因素，使人易让个体对早期压力产生的巨大发展变化，从而导致高成瘾脆弱性，这些发现将为对这种表型的基因组和环境之间的复杂相互作用的详细理解奠定基础。