CNS Genetic Determinants of Alcohol Drinking in Rats Component

该项目的长期目标是更好地了解发生的复杂神经元改变 作为酒精暴露的结果，并在遗传上导致高度饮酒和复发行为， 脆弱的对象。令人信服的证据表明，腹侧被盖区（VTA）和核 在介导乙醇（EtOH）和饮酒的强化作用中，ACB起着重要作用。整体 有待检验的假设是，遗传易感受试者的中脑边缘系统对EtOH敏感 并经历分子神经生物学变化，导致酗酒和复发 行为将在选择性饲养的嗜酒精（P）和高酒精饮用者中检验整个假设 (HAD)行大鼠，使用微穿孔技术分离腹侧被盖区和ACB-壳（sh）。国家- 现有技术的微阵列程序将用于确定（a）VTA中的急性EtOH响应基因， ACB-sh，和（B）长期自我饮酒导致的基因表达变化，并持续存在 在没有酒精的情况下。其中两个目标将确定基因是不同的反应乙醇， 对EtOH反应不同并具有不同饮酒特征的大鼠品系，即，P和 HAD大鼠及其低酒精消耗的对应物，酒精非偏好（NP）和低酒精饮用 (LAD)大鼠另外两个目标将使用操作技术来确定乙醇自我管理的影响 通过P和HAD大鼠对VTA和ACB-sh基因表达的影响，以及是否有一些 在不存在EtOH的情况下，由慢性EtOH自身给药产生的基因表达的变化持续存在。 后两个目标的结果将识别因长期EtOH自我给药而改变表达的基因 并且可能导致复发。总的来说，该项目的研究结果将提供有价值的 关于EtOH诱导的分子神经生物学变化的信息发生在边缘区域， 易受伤害的个体，并可能导致酗酒行为和酒精复发。等 信息对于确定潜在的治疗药理学治疗是重要的， 减少饮酒和复发。

The long-range objectives of this project are to better understand the complex neuronal alterations that occur as a result of alcohol exposure and contribute to high alcohol drinking and relapse behaviors in genetically vulnerable subjects. Compelling evidence implicates the ventral tegmental area (VTA) and nucleus accumbens (ACB) in mediating the reinforcing effects of ethanol (EtOH) and alcohol drinking. The overall hypothesis to be tested is that the mesolimbic system of genetically vulnerable subjects is sensitive to EtOH and undergoes molecular neurobiological changes that contribute to high alcohol drinking and relapse behavior. The overall hypothesis will be tested in the selectively bred alcohol-preferring (P) and high-alcoholdrinking (HAD) lines of rats, using a micro-punch technique to isolate the VTA and the ACB-shell (sh). Stateof- the-art microarray procedures will be used to determine (a) acute EtOH-responsive genes in the VTA and ACB-sh, and (b) changes in gene expression that result from chronic alcohol self-administration and persist in the absence of alcohol. Two of the aims will determine genes that are differentially responsive to EtOH in lines of rats that respond differently to EtOH and have different alcohol drinking characteristics, i.e., P and HAD rats and their low-alcohol-consuming counterparts, alcohol-non-preferring (NP) and low-alcoholdrinking (LAD) rats. Two other aims will use operant techniques to determine the effects of EtOH selfadministration by P and HAD rats on gene expression in the VTA and ACB-sh, and whether some of the changes in gene expression produced by chronic EtOH self-administration persist in the absence of EtOH. The results of these latter two aims will identify genes that have altered expression due to chronic EtOH selfadministration and may contribute to relapse. Overall, the findings from this project will provide valuable information on EtOH-induced molecular neurobiological changes that occur within limbic regions of vulnerable individuals and may contribute to high alcohol drinking behavior and alcohol relapse. Such information would be important for determining potentially therapeutic pharmacological treatments for reducing alcohol drinking and relapse.