RC1 CRF System, Alcohol Dependence and Inhibition

RC1 CRF 系统，酒精依赖和抑制

• 批准号: 8374951
• 负责人: Andrey E Ryabinin
• 金额: $ 11.51万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8374951
• 关键词: Acute; Address; Affinity; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Animals; Area; Behavior; Behavioral; Behavioral inhibition; Binding; Brain; Brain region; Breeding; CCL18 gene; CRF receptor type 1; CRF receptor type 2; Candidate Disease Gene; Chronic; Clinical Research; Complex; Computer Simulation; Consumption; Convulsions; Corticosterone; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Cues; Data; Databases; Development; Disease; Disinhibition; Epidemiology; Ethanol; Exons; Future; Gene Expression Microarray Analysis; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genotype; Health; Heavy Drinking; Hippocampus (Brain); Human; Impulsive Behavior; Impulsivity; Inbred Strains Mice; Inbreeding; Intake; Measures; Microarray Analysis; Molecular; Mus; Peptide Receptor; Peptides; Pharmacotherapy; Phenotype; Pilot Projects; Plasma; Policies; Predisposition; Prevention; Proteins; Recombinants; Regulation; Research Personnel; Resistance; Rewards; Risk; Role; Seizures; Severities; Signal Transduction; Symptoms; System; Testing; Transgenic Mice; Withdrawal; alcohol exposure; base; behavioral genomics; corticotropin releasing factor-binding protein; discounting; drinking; genetic variant; human APEX1 protein; immunoreactivity; neuroadaptation; preference; receptor; research study; response; trait; urocortin

Alcoholism is a health disorder characterized by a progression from experimentation, to excessive intake, and ultimately alcohol dependence accompanied by compulsive alcohol consumption. The relationship between alcohol consumption and dependence is complex. For example, it is assumed that increased alcohol intake associated with alcohol dependence leads to increased symptoms of physical withdrawal. However, studies performed in the PARC showed that natural genetic variants (e.g. inbred mouse strains) with increased susceptibility to high alcohol withdrawal convulsions tend to avoid alcohol consumption. More recent PARC studies found a strong positive genetic correlation between measures of behavioral disinhibition in the Go/No-go task with measures of alcohol withdrawal severity. This component uses a candidate gene approach to test the contribution of the corticotropin releasing factor (CRF) system to these relationships. The CRF system is known to contribute to mechanisms surrounding alcohol dependence. Our preliminary studies suggest that the CRF system is involved in regulation of alcohol withdrawal and behavioral inhibition. The CRF system contains four peptides: CRF, urocortin (Ucn)1, Ucn2 and Ucn3, two types of CRF receptors, and the CRF-binding protein. The role of genes encoding these peptides and proteins in ethanol withdrawal or in impulsive behaviors has not been investigated. The four aims of this component propose to bridge this gap by: 1) investigating withdrawal-induced convulsions after acute and chronic ethanol in CRF, Ucnl, CRFI receptor, CRF2 receptor KO mice and their wildtype (WT) llttermates, 2) investigating behavioral inhibition in the Go/No-go task in CRF, Ucnl, CRFI receptor, CRF2 receptor KO mice, and their WT llttermates, 3) identifying gene networks contributing to regulation of behavioral inhibition and alcohol withdrawal by expression microarray analysis in CRF, Ucnl, CRFI receptor, CRF2 receptor KO mice and their WT controls, 4) identifying polymorphisms in genes encoding CRF, Ucnl, Ucn2, Ucn3, CRFI, CRF2 and CRF-BP in inbred strains of mice known to have differences in signs of ethanol-induced withdrawal and measures of disinhibition in the Go/No-go task, and to test associations of these polymorphisms with these and other ethanol-related phenotypes.

酗酒是一种健康障碍，其特征是从尝试到过量摄入，最终形成酒精依赖并伴有强迫性饮酒。饮酒与依赖之间的关系很复杂。例如，假设与酒精依赖相关的酒精摄入量增加会导致身体戒断症状增加。然而，在帕洛阿尔托研究中心进行的研究表明，自然遗传变异（例如近交 小鼠品系）对高度酒精戒断性惊厥的敏感性增加，倾向于避免饮酒。最近的 PARC 研究发现，Go/No-go 任务中的行为去抑制测量值与酒精戒断严重程度测量值之间存在很强的正相关性。该组件使用候选基因方法来测试促肾上腺皮质激素释放因子 (CRF) 系统对这些关系的贡献。 众所周知，CRF 系统有助于酒精依赖的机制。我们的初步研究表明，CRF 系统参与酒精戒断和行为抑制的调节。 CRF 系统包含四种肽：CRF、尿皮质素 (Ucn)1、Ucn2 和 Ucn3、两种类型的 CRF 受体以及 CRF 结合蛋白。编码这些肽和蛋白质的基因在乙醇戒断或冲动行为中的作用尚未得到研究。该部分的四个目标旨在通过以下方式弥补这一差距：1) 研究 CRF、Ucnl、CRFI 受体、CRF2 受体 KO 小鼠及其野生型 (WT) 小鼠在急性和慢性乙醇后戒断诱发的惊厥，2) 研究行为抑制在 CRF、Ucnl、CRFI 受体、CRF2 受体 KO 小鼠及其 WT 小鼠的 Go/No-go 任务中，3) 识别有助于调节行为抑制的基因网络通过表达微阵列分析 CRF、Ucnl、CRFI 受体、CRF2 受体 KO 和酒精戒断 小鼠及其 WT 对照，4) 鉴定近交系小鼠中编码 CRF、Ucnl、Ucn2、Ucn3、CRFI、CRF2 和 CRF-BP 的基因的多态性，这些近交系小鼠已知在乙醇诱导的戒断症状和去抑制测量方面存在差异。通过/不通过任务，并测试这些多态性与这些和其他乙醇相关表型的关联。