CELLULAR MECHANISMS OF ACTION OF ALCOHOL

酒精的细胞作用机制

基本信息

批准号：
6873773
负责人：
TOSHIO NARAHASHI
金额：
$ 36.75万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-07-01 至 2007-09-30
项目状态：
已结题

项目摘要

EXCEED THE SPACE PROVIDED. The long-term goal of this study is to elucidate the mechanism of action of ethanol on neuronal ion channels which will provide the basis for understanding the physiological and behavioral changes associated with alcohol drinking, the toxic action of alcohol, and alcoholism including its cure. The specific aims of the renewal application of this grant are to elucidate the mechanisms of action of ethanol on neuronal nicotinic acetylcholine receptors (nnAChRs). A number of neuroreceptors and ion channels have been shown to be affected by ethanol during the past 10years or so. Various behavioral effects of ethanol including rewarding and reinforcement are known to be mediated by GABAA and dopamine receptors among others. It is also well established that the nnAChR system modulates the release of various transmitters including GABA and dopamine. We have recently demonstrated using rat cortical neurons that ethanol at 3-10 mM and above potentiates a-bungarotoxin (a-BuTX)-insensitive ACh- induced currents while weekly inhibiting a-BuTX-sensitive currents. Thus, significant ethanol modulation of nnAChRs will lead to a cascade of synaptic events involvingvarious transmitters, resulting in complex behavioral changes. While our efforts have been devoted mostly to the ethanol modulation of GABAA receptors up to the current grant period, we have decided to pursue the action of ethanol on nnAChRs during the coming grant period. Rat cortical neurons in long-term primary culture and human embryonic kidney cells expressing various nnAChR subunits will be used for whole-cell and single-channel patch clamp experiments. The specific aims are as follows: 1) The mechanism of potentiation of a-BuTX-insensitive ACh-induced currents by ethanol will be elucidated. 2) Novel dual effects of n-alcohols with varying chain length (flip-flop), which we discovered recently, will be analyzed. 3) Alcohol modulation of the kinetics of ACh-induced currents will be studied. 4) Alcohol-induced GABA release via stimulation of nnAChRswill be studied using brain slice and cultured neuron network preparations. The results of these experiments are expected to provide useful information about the mechanism of action of alcohol at the receptor/channel level. PERFORMANCE SITE ========================================Section End===========================================

超过提供的空间。这项研究的长期目标是阐明乙醇对神经元离子通道的作用机理，这将为理解与饮酒，酒精的有毒作用以及酒精中毒在内的生理和行为变化提供基础。该赠款的更新应用的具体目的是阐明乙醇对神经元烟碱乙酰胆碱受体（NNACHRS）的作用机理。在过去的10年左右的时间里，许多神经受体和离子通道已受到乙醇的影响。已知乙醇（包括奖励和增强）的各种行为影响是由GABAA和多巴胺受体介导的。还可以很好地确定NNACHR系统可以调节包括GABA和多巴胺在内的各种发射器的释放。我们最近使用大鼠皮质神经元证明，在3-10 mm及以上的乙醇增强了A-甲状腺毒素（A-butx）不敏感的ACH诱导的电流，而每周抑制A-Butx敏感的电流。因此，NNACHRS的显着乙醇调节将导致一系列涉及变速箱的突触事件，从而导致复杂的行为变化。虽然我们的努力主要用于直至当前赠款期的GABAA受体的乙醇调节，但我们决定在未来的赠款期内采取乙醇对NNACHRS的行动。长期原发性培养物和表达各种NNACHR亚基的人类胚胎肾细胞中的大鼠皮质神经元将用于全细胞和单渠道贴片夹实验。具体目的如下：1）将阐明乙醇对A-butx不敏感的ACH诱导的电流增强的机理。 2）将分析具有不同链长（触发器）的N-醇的新型双重效应，我们将被分析。 3）将研究对ACH诱导电流动力学的酒精调节。 4）通过使用脑切片和培养的神经元网络制剂来研究酒精诱导的GABA释放。这些实验的结果有望提供有关在受体/通道水平上酒精作用机理的有用信息。表演站点=============================================================================================