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。对乙醇的耐受性和身体依赖性的分子基础尚待确定。有证据表明 GABAA 和 NMDA 受体参与乙醇的行为影响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，长期乙醇和 CIE 治疗会产生 GABAA 和 NMDA 受体亚基的差异改变，其中一些亚基增加，一些亚基减少和/或一些亚基没有变化。这可能导致受体亚型/受体组装体改变，和/或影响其中一些亚基的磷酸化状态。我们将利用体外和体内方法。我们将检查慢性和 CIE 治疗对 GABAA 和 NMDA 受体亚基 mRNA 和多肽水平的影响，慢性乙醇治疗对天然 GABAA 和 NMDA 受体组件的影响，并确定酪氨酸激酶介导的 GABAA 和 NMDA 受体亚基磷酸化是否存在受急性、慢性和/或 CIE 治疗的影响。我们将利用培养的皮质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中枢神经系统细胞类型的多样性，并为研究慢性药物效应提供了理想的体外模型。对于天然受体组装研究，我们将对大鼠进行长期乙醇治疗并检查离散大脑区域的变化。这是因为我们将探索成人天然受体组件的变化，并检查大脑中包含不同 GABAA 和 NMDA 受体组件的几个区域的影响。将检查以下具体目标： 1) CIE 治疗对 GABAA 和 NMDA 受体亚基 mRNA 和多肽水平有何影响？ 2) 哪些天然 GABAA 和 NMDA 受体组件会受到长期乙醇治疗的影响？ 3) 急性、慢性和 CIE 治疗是否会改变 Fyn 酪氨酸激酶介导的 NMDA 和 GABAA 受体磷酸化？表演网站==========================================部分结束====== =======================================