Regulation of Ethanol Effects on Synaptic Transmission

乙醇对突触传递影响的调节

• 批准号: 7035677
• 负责人: MARISA ROBERTO
• 金额: $ 31.53万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-05 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035677
• 关键词: GABA receptor; alcoholism /alcohol abuse; amygdala; biological signal transduction; brain; calcium channel; corticotropin releasing factor; ethanol; gamma aminobutyrate; laboratory rat; microdialysis; neural plasticity; neural transmission; neuropharmacology; psychopharmacology; reinforcer; sectioning; tissue /cell preparation; voltage /patch clamp

DESCRIPTION (provided by applicant): The primary objective of this project is to understand the neuronal, cellular and synaptic mechanisms underlying alcohol intoxication and dependence, using intracellular and patch-clamp recording in brain slices and in vivo microdialysis. A central hypothesis is that adaptive changes in synapses cause alcohol dependence. We also hypothesize that neuroadaptations in the GABAergic system play a major role in alcohol reinforcing actions. Our past research has centered on neurons of the central nucleus of the amygdala (CeA), because behavioral studies suggest that the amygdala, and its connections to the NAcc and bed nucleus of the stria terminalis, termed the 'extended amygdala,' play a major role in the acute reinforcing effects of ethanol and in the anxiogenic response to ethanol withdrawal. Our planned studies are based on the following rationale: 1) Acute ethanol markedly enhances GABAergic neurotransmission in CeA through the activation of CRF1 receptors. We present the first direct evidence that this ethanol-induced increase in GABAergic response is in part due to increased GABA release. 2) Our preliminary data also indicate that chronic ethanol treatment (GET) greatly enhances baseline GABAergic tone in the CeA. 3) Despite this large increase in basal GABA release, there is a lack of tolerance to acute ethanol-induced GABA release in CeA of GET rats. 4) Our preliminary evidence of neuroadaptive changes in the CRF system and in GABAB receptors in modulating synaptic efficacy following GET. Therefore in this application we propose to study the cellular and molecular basis of ethanol interactions with GABAergic transmission using a multidisciplinary approach. Specific Aims 1 and 2 will test, in vitro and in vivo, the possible involvement of presynaptic CRF receptors, membrane Ca++ channel and their transduction mechanisms coupled to the regulation of GABA release machinery in the effect of acute (Aim 1) and chronic (Aim 2) ethanol in CeA neurons. Understanding the specific presynaptic mechanisms underlying ethanol enhancement of GABA IPSPs induced by both acute and chronic ethanol represents a new challenge for alcohol research and a possible target for the development of therapeutic compounds for the treatment of alcoholism.

描述（由申请人提供）：本项目的主要目的是了解酒精中毒和依赖的神经元，细胞和突触机制，使用细胞内和膜片钳记录在脑切片和体内微透析。一个中心假设是，突触的适应性变化导致酒精依赖。我们还假设GABA能系统的神经适应在酒精强化作用中起主要作用。我们过去的研究集中在杏仁核中央核（CeA）的神经元，因为行为学研究表明，杏仁核，其连接到NAcc和床核的终纹，被称为“扩展杏仁核”，发挥了重要作用，在急性酒精强化效应和乙醇戒断的焦虑反应。我们计划的研究基于以下原理：1）急性乙醇通过激活CRF1受体显著增强CeA中的GABA能神经传递。我们提出了第一个直接证据，表明乙醇诱导的GABA能反应增加部分是由于GABA释放增加。2)我们的初步数据还表明，慢性乙醇治疗（GET）大大提高了基线GABA能紧张的CeA。3)尽管这种大的增加，在基础GABA的释放，有急性乙醇诱导的GABA释放的GET大鼠CeA缺乏耐受性。4)我们的初步证据表明，在GET后，CRF系统和GABAB受体在调节突触功效方面发生了神经适应性变化。因此，在本申请中，我们建议使用多学科方法研究乙醇与GABA能传递相互作用的细胞和分子基础。具体目标1和2将在体外和体内测试突触前CRF受体、膜Ca++通道及其与GABA释放机制调节偶联的转导机制在CeA神经元中急性（Aim 1）和慢性（Aim 2）乙醇效应中的可能参与。了解特定的突触前机制的乙醇增强GABA的IPSPs诱导的急性和慢性乙醇是一个新的挑战，酒精的研究和一个可能的目标，用于治疗酒精中毒的治疗化合物的发展。