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Chronic/Intermittent Ethanol GABA and NMDA Receptors

慢性/间歇性乙醇 GABA 和 NMDA 受体

基本信息

批准号：
6915776
负责人：
MAHARAJ K TICKU
金额：
$ 28.9万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2007-06-30
项目状态：
已结题

项目摘要

EXCEED THE SPACE PROVIDED. The molecular basis underlying the development of tolerance and physical-dependence to ethanol is yet to be defined. There is evidence for involvement of GABAA and NMDA receptors in the behavioral effects of ethanol, and in the development of tolerance and physical-dependence. Our studies are aimed at defining the potential molecular adaptive mechanisms by which chronic ethanol and chronic intermittent (CIE) ethanol treatments affect GABAA and NMDA receptor systems. Our main hypothesis is that chronic ethanol and CIE treatments produce differential alterations of the GABAA and NMDA receptor subunits, with increases in some, decreases in some and/or no changes in some of the subunits. This could result in altered receptor isoforms/ receptor assemblies, and/or affect the phosphorylation state of some of these subunits. We will utilize both in vitro and in vivo approaches. We will examine the effects of chronic and CIE treatments on subunit mRNA and polypeptide levels of GABAA and NMDA receptors, effects of chronic ethanol treatment on native GABAA and NMDA receptor assemblies, and determine if tyrosine-kinase mediatedphosphorylation of the GABAA and NMDA receptor subunits is affected by acute, chronic and/or CIE treatments. We will utilize cultured cortical neurons and whole animal studies. A major advantage of the cultured neurons is that they reflect the diversity of cell types of intact CNS, and provide an ideal in vitro model to study chronic drug effects. For native receptor assembly studies, we will utilize chronic ethanol treatment to rats and examine changes in discrete brain regions. This is necessitated by the fact that we will explore changes in adult native receptor assemblies, and examine effects in several regions of the brain that contain different receptor assemblies of GABAA and NMDA receptors. The following specific aims will be examined: 1) What are the consequences of CIE treatment on the GABAA and NMDA receptor subunit mRNA and polypeptide levels? 2) Which native GABAA and NMDA receptor assemblies are affected by chronic ethanol treatment? and 3) Do acute, chronic, and CIE treatments alter the Fyn-tyrosine kinase mediated phosphorylation of the NMDA and GABAA receptors? PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。对乙醇耐受性和身体依赖性发展的分子基础尚未确定。有证据表明GABAA和NMDA受体参与乙醇的行为效应，以及耐受性和身体依赖性的发展。我们的研究旨在确定慢性乙醇和慢性间歇性（CIE）乙醇治疗影响GABAA和NMDA受体系统的潜在分子适应机制。我们的主要假设是，慢性乙醇和CIE治疗产生的GABAA和NMDA受体亚基的差异改变，在一些增加，减少和/或没有变化的一些亚基。这可能导致受体亚型/受体组装体改变，和/或影响这些亚基中的一些亚基的磷酸化状态。我们将利用体外和体内方法。我们将研究慢性和CIE处理对GABAA和NMDA受体亚基mRNA和多肽水平的影响，慢性乙醇处理对天然GABAA和NMDA受体组装的影响，并确定酪氨酸激酶介导的GABAA和NMDA受体亚基磷酸化是否受到急性，慢性和/或CIE处理的影响。我们将利用培养的皮层神经元和整个动物研究。培养的神经元的一个主要优点是它们反映了完整CNS的细胞类型的多样性，并且为研究慢性药物作用提供了理想的体外模型。对于天然受体组装研究，我们将利用慢性乙醇处理大鼠，并检查离散脑区的变化。这是必要的，因为我们将探索成人天然受体组件的变化，并检查包含GABAA和NMDA受体的不同受体组件的大脑几个区域的影响。1）CIE处理对GABAA和NMDA受体亚单位mRNA和多肽水平的影响是什么？2)哪些天然GABAA和NMDA受体组件受到慢性乙醇处理的影响？和3）急性、慢性和CIE治疗是否改变Fyn-酪氨酸激酶介导的NMDA和GABAA受体的磷酸化？性能现场=