Effect of CRF1 Receptor Genotype and Stress on Anxiety and Alcohol Endophenotypes

描述(由申请人提供)：焦虑症和酗酒之间的发病率很高，大多数研究结果表明，焦虑症先于酗酒。促肾上腺皮质激素释放因子(CRF)是一种在应激过程中释放的神经肽，它既影响焦虑样的内表型，也影响酒精的内表型。我们发现Wistar-京都(WKY)和棕色挪威(BN)大鼠品系在10号染色体CRF1受体基因(CRHR1)上游的保守区存在以前没有描述过的多态性。在这个探索性项目中，将解决三个特定的目标。具体目的1.确定：1)大鼠基线或压力诱导的焦虑样行为水平的压力依赖差异是否预测酒精消费的基线和/或压力诱导的变化；2)大鼠依赖压力的酒精消费基线水平是否预测压力诱导的饮酒量增加。我们还将研究该基因多态对多个脑区CRF基因水平的影响。最后，我们将对这些大鼠品系中CRF1受体的编码区进行额外的测序，并筛选杂交大鼠品系，以确定WKY变体可能有多常见。具体目的2.建立WKY染色体为10的BN系和BN染色体为10的WKY系。进一步测定WKY和BN大鼠CRF1受体的编码区序列。检测WKY和BN脑内CRF1基因表达的丰度。目的：检测WKY 10号染色体变异在异交大鼠中的共性。具体目的3.检验大鼠对酒精行为影响的敏感性是否存在品系依赖差异。因此，我们试图研究基线焦虑和酒精样内表型之间的关系，以及这两个品系大鼠基线和应激诱导的内表型变化之间的关系。利用我们培育的回交大鼠，我们将开始探索CRF1受体基因(CRHR1)10号染色体上游保守区的多态的功能意义。 公共卫生相关性：焦虑和酒精使用障碍之间存在高度的共病，与应激相关的神经肽和促肾上腺皮质激素释放因子似乎都参与了这两种疾病。这些研究的目的是研究压力与不同CRF基因型对焦虑和酒精使用的内表型的关系。

DESCRIPTION (provided by applicant): There is a high degree of co-morbidity between anxiety disorders and alcohol abuse, with the results of most studies suggesting that anxiety disorders predate alcohol abuse. Corticotropin-releasing factor (CRF) is a neuropeptide that is released during stress and the peptide effects both anxiety-like endophenotypes and alcohol endophenotypes. We have found that the Wistar-Kyoto (WKY) and Brown Norway (BN) rat strains have a polymorphism that has not previously been described, in the conserved region upstream of the CRF1 receptor gene (CRHR1) on chromosome 10. Three Specific Aims will be addressed in this exploratory project. Specific Aim 1. To determine: 1) Whether rat strain-dependent differences in baseline or stress-induced levels of anxiety-like behaviors predict baseline and/or stress-induced changes in alcohol consumption; 2) Whether rat strain-dependent baseline levels of alcohol consumption predict stress-induced increases in consumption. We will also examine the effect of the polymorphism on CRF mRNA levels in a number of brain regions. Finally, we will perform additional sequencing of the coding region of the CRF1 receptor in these rat strain, and screen outbred rat strains to identify how common the WKY variant might be. Specific Aim 2. To develop a BN line with a WKY chromosome 10, and a WKY line with a BN chromosome 10. To further sequence the coding region of the CRF1 receptor in WKY and BN rats. To examine the abundance of CRF1 mRNA in several regions of WKY and BN brain. To examine the commonality of the WKY chromosome 10 variant in outbred rats. Specific Aim 3. To examine whether there are rat strain-dependent difference in sensitivity to the behavioral effects of alcohol. Thus, we seek to examine the relationships among baseline anxiety- and alcohol- like endophenotypes, as well as the relationships between baseline and stress-induced changes in the endophenotypes in these two strains of rat. Using the backcrossed rats we develop, we will begin to explore the functional significance of the polymorphism in the conserved region upstream of the CRF1 receptor gene (CRHR1) on chromosome 10. Public Health Relevance: There is a high degree of comorbidity between anxiety and alcohol use disorders, and the stress-related neuropeptide, corticotropin-releasing factor appears to be involved in both. The purpose of these studies is to examine the relationship between stress and different CRF genotypes on anxiety and alcohol use endophenotypes.