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。

基本信息

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
项目类别：
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

项目摘要

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）：可卡因成瘾是遗传和环境因素相互作用产生的复杂表型。该提案的总体基本原理是，特定的多基因背景与特定的经历相互作用，以确定可卡因反应性，使个体或多或少容易对可卡因成瘾。我们的目标是阐明调节早期环境经历改变成人对可卡因反应能力的遗传因素。广泛的研究集中于描绘增加可卡因反应性的特定早期（以及成人）环境条件。流行病学数据表明，在自然灾害和人为灾难期间，子宫内神经精神疾病的发病率大幅增加。在动物研究中，产前压力会产生成年表型，包括对可卡因精神运动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更多的可卡因寻求，这表明早期生活压力的历史会产生更大的脆弱性可卡因成瘾。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反应性。临床和家族研究表明，可卡因成瘾具有显着的遗传性，最低限度的估计表明，遗传变异性可以解释个体成瘾脆弱性变异性的 30%。在动物研究中，观察到可卡因对小鼠品系的行为和生理影响存在显着差异。此外，小鼠基因组的作图以及重组近交小鼠品系组的构建现在可以定量分析特定遗传位点对可卡因反应性的贡献。相反，有新的证据表明基因-环境相互作用在确定可卡因反应性方面，目前，我们预测个体可卡因反应性的能力的一个主要障碍是缺乏对基因与环境之间相互作用的系统研究，而对这些因素的确定将有助于先验确定有可卡因成瘾风险的个人。因此，现在是时候通过纳入基因-环境相互作用的系统研究来扩展数量性状位点分析，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位点基因。本提案的总体目标是利用小鼠模型对成瘾易感性的早期环境调节进行分析。目标 1 将评估两种表现出不同可卡因反应性的小鼠品系（C57BL/6 和 DABA/2J）及其 F1 后代之间由产前应激 (PNS) 引起的可卡因反应性差异。这将包括评估剂量反应曲线中的应变 x PNS 变化，不仅包括精神兴奋剂，还包括可卡因的奖励特性，以及对轻微心理和身体压力源的反应性以及重复接触这些反应中的神经适应。为了更直接地研究特定遗传因素（在染色体位点水平）与早期环境应激之间的相互作用，目标 2 将在一组源自 C57BL/6 和 DBA 的重组自交系菌株中检查三七总皂苷 (PNS) 对可卡因反应性的影响/2 亲本系，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 PNS 诱导的可卡因反应性变化相关。此外，这些反应的对照数据将用于复制和扩展之前的 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介质，为基因-环境相互作用提供新的分析。公共卫生相关性：由于复杂的遗传和环境相互作用，药物成瘾的易感性存在明显的个体差异，但是，对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，这两个模型系统检查遗传变异（重组近交系小鼠系）的贡献和不利的早期环境条件（产前应激）的贡献。该项目的目标是在特定染色体位点水平上识别遗传因素，这些因素使个体容易遭受早期压力导致的高度成瘾脆弱性所产生的巨大发育变化，这些发现将为详细了解复杂的遗传因素奠定基础。基因组和环境之间的相互作用决定了这种表型。