Ethanol Mechanisms in GABAAR Gene Targeted Mice

GABAAR 基因靶向小鼠的乙醇机制

基本信息

批准号：
8462173
负责人：
Gregg E. Homanics
金额：
$ 39.84万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462173
关键词：
Abbreviations Acute Address Alcohol abuse Alcohol consumption Alcoholism Amygdaloid structure Anxiety Behavior Behavioral Biochemical Biological Assay Brain Brain region Cataloging Catalogs Cells Cerebrospinal Fluid Chronic Dependence Development Epigenetic Process Ethanol Exhibits Gene Expression Gene Expression Profile Gene Targeting Genes Genetically Engineered Mouse Goals Grant Hippocampus (Brain)Histone Acetylation Histone Deacetylase Knock-out Lateral Lead Long-Term Effects Measures Medical Methylation Modeling Molecular Mus Mutation Neurobiology Nucleus Accumbens Phenotype Phosphorylation Play Point Mutation Property Research Role Seizures Societies Synapses Testing Withdrawal Work addiction chromatin immunoprecipitation drinking effective therapy histone modification neuroadaptation neurophysiology non-alcoholic preference problem drinker public health relevance receptor research study socioeconomics synaptic inhibition treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Ethanol (EtOH) is abused for both its positive and negative reinforcing effects. Although much is known about the neurobiological substrates underlying EtOH's positive reinforcing effects, relatively little is known about the neurophysiological mechanisms and brain regions that contribute to EtOH's negative reinforcing properties. In this proposal, we take advantage of a genetically engineered mouse line that exhibits increased sensitivity to some of EtOH's negative reinforcing effects. We previously demonstrated that these GABAA receptor alpha1 subunit gene knockin mice exhibit an increase in several measures of acute EtOH-induced anxiolysis and marked increases in EtOH withdrawal seizures. The experiments proposed will integrate neurobiological and behavioral approaches, in global and brain region specific knockin mice, to dissect the mechanisms through which chronic EtOH exposure and withdrawal lead to functional deficits in GABAergic synaptic inhibition. These aims will address the hypothesis that EtOH-induced GABAergic synaptic adaptation in the hippocampus and basolateral amygdala lead to brain-region specific alterations in anxiety-like behavior, withdrawal seizures, and dependence-induced escalations in EtOH drinking. On a more basic level, EtOH alters gene expression. Undoubtedly such EtOH- induced neuroadaptations are also intimately involved in the long-term effects of EtOH on the brain. This is especially true for the transition from recreational drinking to EtOH abuse and alcoholism; the brains of alcoholics have a transcriptome that differs from non-alcoholics. While numerous studies have catalogued changes in EtOH-induced gene expression, a very basic and profound question has not yet been addressed. What is the mechanism by which EtOH reprograms the brain transcriptome? We hypothesize that EtOH-induced epigenetic changes are the fundamental mechanism responsible for this important effect of EtOH. Thus, the final aim will investigate the epigenetic effects of EtOH.

描述（由申请人提供）：乙醇（ETOH）因其积极和负增强作用而被滥用。尽管对ETOH的阳性增强作用的神经生物学底物知之甚少，但对有助于ETOH负增强特性的神经生理机制和大脑区域知之甚少。在此提案中，我们利用了一条基因工程的小鼠系列，该系列对ETOH的某些负增强作用表现出更高的敏感性。我们先前证明了这些GABAA受体α1亚基基因敲击蛋白小鼠的急性ETOH诱导的抗焦虑症的多种测量和ETOH戒断癫痫发作的明显增加。提出的实验将在全球和大脑区域特异性敲门蛋白小鼠中整合神经生物学和行为方法，以剖析慢性EtOH暴露和戒断导致GABA能突触抑制的功能缺陷的机制。这些目的将解决以下假设：ETOH诱导的海马和基底外侧杏仁核中的GABA能突触适应会导致焦虑症行为，戒断癫痫发作以及依赖性诱导EtOH饮酒的升级。在更基本的水平上，EtOH改变了基因表达。毫无疑问，这种eTOH诱导的神经适应也与ETOH对大脑的长期作用密切相关。从娱乐性饮酒到Etoh滥用和酒精中毒的过渡尤其如此。酗酒者的大脑具有与非酒精剂不同的转录组。尽管许多研究已经分类了ETOH诱导的基因表达的变化，但尚未解决一个非常基本和深刻的问题。 ETOH重新编程脑转录组的机制是什么？我们假设ETOH诱导的表观遗传变化是负责ETOH的这种重要作用的基本机制。因此，最终目标将研究EtOH的表观遗传效应。