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

描述（由申请人提供）：焦虑障碍和酒精滥用之间存在高度的共发病，大多数研究结果表明焦虑障碍早于酒精滥用。促肾上腺皮质激素释放因子（CRF）是一种在应激状态下释放的神经肽，它影响焦虑样内表型和酒精样内表型。我们发现Wistar-Kyoto （WKY）和Brown Norway （BN）大鼠菌株在10号染色体上CRF1受体基因（CRHR1）上游的保守区域具有先前未被描述的多态性。这个探索性项目将解决三个具体目标。具体目标确定：1)大鼠品系依赖性的基线或应激诱导的焦虑样行为水平差异是否能预测基线和/或应激诱导的酒精消耗变化；2)大鼠品系依赖的酒精消耗基线水平是否预测应激诱导的酒精消耗增加。我们还将研究多态性对大脑多个区域中CRF mRNA水平的影响。最后，我们将对这些大鼠菌株的CRF1受体编码区进行额外的测序，并筛选近交大鼠菌株，以确定WKY变异的常见程度。具体目标2。培养具有10号WKY染色体的BN系和具有10号BN染色体的WKY系。进一步对WKY和BN大鼠的CRF1受体编码区进行测序。目的：检测WKY和BN脑多个区域中CRF1 mRNA的丰度。目的：探讨远交种大鼠WKY 10号染色体变异的共性。具体目标3。研究大鼠对酒精行为影响的敏感性是否存在品系依赖性差异。因此，我们试图检查基线焦虑和酒精样内表型之间的关系，以及这两种大鼠中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10号染色体上CRF1受体基因（CRHR1）上游保守区域多态性的功能意义。

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.