GENETIC BASIS FOR ETHANOL'S HEDONIC EFFECTS

乙醇的享乐效果的遗传基础

• 批准号: 6097716
• 负责人: CHRISTOPHER L CUNNINGHAM
• 金额: $ 18.89万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6097716
• 关键词: alcoholic beverage consumption; animal breeding; animal genetic material tag; avoidance behavior; behavior test; behavioral /social science research tag; behavioral genetics; conditioning; ethanol; gene frequency; genetic markers; genetic models; genetic strain; genotype; laboratory mouse; linkage mapping; model design /development; motivation; paired stimuli; pharmacogenetics; phenotype; preference; quantitative trait loci; reinforcer; taste

A broad goal of this Center is to combine the use of Quantitative Trait Loci (QTL) linkage mapping techniques with several different animal genetic models to identify and localize genes affecting behavioral and pharmacological responses to ethanol. Our previous studies have revealed substantial genetic variability within the BXD recombinant inbred strains in three different ethanol phenotypes believed to be relevant to understanding the rewarding and aversive effects of ethanol: ethanol drinking, conditioned place preference, and conditioned taste aversion. Moreover, our studies suggest partial overlap in the genetic mechanisms influencing these behaviors and QTL analyses have identified several chromosomal regions of potential interest. However, because of limitations imposed by the statistical strategy used for QTL mapping, these loci must be considered provisional until they are confirmed by additional studies. Thus, the goal of this Component Project is to verify several of the strongest QTL identified for each of these ethanol reward phenotypes (e.g., withdrawal, hypothermia, ataxia). Our primary strategy for QTL verification involves testing of F2 mice derived from the BXD progenitor strains, C57BL/6 (B6 and DBA/2 (D2), and genotyping high responders and low responders at markers flanking the provisional QTL. The importance of QTL verified in this population will be evaluated further in studies in which F2 mice are selectively bred on the basis of their genotype at markers flanking a verified QTL (Genotypic Selection). These mice will then be tested for differences in the behavioral phenotypes to determine the role of allelic status at the QTL of interest. Genotypic selection will also sere as the starting point for the development of Congenic Strains in which either the B6 or D2 allele at a target QTL is transferred to the background of the opposite progenitor strain by repeated backcrossing. These oncogenic strains will facilitate future research aimed at identifying specific genes influencing each behavioral phenotype. Finally, to evaluate the genetic interrelatedness of these behavioral phenotypes, we will examine correlated responses to selection in mouse lines that have been selectively bred for differences in sensitivity to ethanol' behavioral effects in each of these tasks (Phenotypic Selection). These selected liens will also be genotyped at appropriate markers to determine whether divergence in the behavioral phenotype is accompanied by divergence in gene frequency. Once candidate genes have been identified in the mouse, homologous genes or regions of the human chromosome can be studied in detail to determine whether they are linked to alcoholism.

该中心的广泛目标是结合定量性状的使用 基因座（QTL）连锁映射技术与几种不同的动物遗传 识别和定位影响行为和本地化的模型 对乙醇的药理反应。 我们以前的研究表明 BXD重组近交菌株内的实质遗传变异性 在三种不同的乙醇表型中，被认为与 了解乙醇的有益和厌恶作用：乙醇 饮酒，条件的地方偏好和条件味觉厌恶。 此外，我们的研究表明遗传机制部分重叠 影响这些行为和QTL分析已经确定了几个 潜在兴趣的染色体区域。 但是，由于局限性 这些基因座由用于QTL映射的统计策略强加了 在通过其他研究确认临时性之前，被视为临时性。 因此，该组件项目的目标是验证几个 为这些乙醇奖励表型中的每一种都确定了最强的QTL（例如 戒断，体温过低，共济失调）。 我们QTL的主要策略 验证涉及测试从BXD祖细胞得出的F2小鼠 菌株，C57BL/6（B6和DBA/2（D2），以及基因分型高响应者和低响应者 临时QTL的标记的响应者。 QTL的重要性 在该人群中得到验证的研究将进一步评估 F2小鼠在标记处有选择性地繁殖出其基因型 侧面验证的QTL（基因型选择）。 这些老鼠将是 测试了行为表型的差异以确定角色 QTL的等位基因状态。 基因型选择也将 作为开发先天性菌株的起点 目标QTL处的B6或D2等位基因转移到背景 通过重复反向交叉通过相反的祖细胞应变。 这些 致癌菌株将促进未来的研究，以识别 影响每个行为表型的特定基因。 最后，评估 这些行为表型的遗传相互关系，我们将 检查对鼠标系中选择的相关响应 有选择地育出了对乙醇行为敏感性的差异 这些任务中的每一个（表型选择）的影响。 这些选择 留置权也将以适当的标记为基因分型，以确定是否是否 行为表型的差异伴随着基因的发散 频率。 一旦在小鼠中鉴定出候选基因， 可以研究人类染色体的同源基因或区域 细节以确定它们是否与酒精中毒有关。