MOLECULAR BASIS FOR GENDER SELECTIVE EFFECTS OF ETHANOL

乙醇性别选择性效应的分子基础

• 批准号: 6371487
• 负责人: Leslie L Devaud
• 金额: $ 13.12万
• 依托单位: IDAHO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-27 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6371487
• 关键词: GABA receptor; NMDA receptors; alcoholic beverage consumption; autoradiography; behavioral /social science research tag; blood tests; cerebral cortex; dizocilpine; drug withdrawal; ethanol; gender difference; gene expression; glutamate receptor; hormone regulation /control mechanism; laboratory rat; neurohormones; neuropharmacology; neuropsychological tests; neuropsychology; protein structure function; radioimmunoassay; receptor binding; receptor expression; steroid hormone; western blottings

The goal of this proposal is to characterize the molecular basis for gender differences underlying ethanol dependence. The objective is to test the hypothesis that gender influences neuroadaptations of GABA and glutamatergic systems elicited by chronic ethanol exposure. GABAA and NMDA receptors are key sites in the brain mediating the effects of ethanol. Ethanol dependence results in subunit selective alterations in gene expression and function for both GABAA and NMDA receptors. We have recently found profound gender differences in the effects of chronic ethanol consumption on GABAA receptor alpha and NMDA NR1 subunit expression. This shows that gender impacts the effects of ethanol dependence on gene expression for these two key neurotransmitter systems. This suggests that neuroadaptations associated with ethanol dependence and withdrawal may be dependent on the hormonal context of the ethanol exposure. However, there is little evidence showing a direct association between ethanol dependence and withdrawal behaviors and the molecular changes observed for GABAA and NMDA receptors. The proposed studies will investigate the molecular basis for gender differences in the effects of ethanol dependence and withdrawal by correlating the development of and recovery from ethanol dependence with changes in gene expression and receptor regulation. This proposal will test the hypothesis that ethanol dependence induces gender-selective alterations in 1) GABAA receptor regulation, function and gene expression, 2) NMDA receptor regulation, function and gene expression, and 3) levels of several key neuroactive steroids. We will determine whether these alterations show a temporal correlation with behavioral manifestations of ethanol dependence and withdrawal. These studies are particularly important as the expression of neuroadaptations to chronic ethanol consumption varies according to gender, even though both genders display similar behavioral signs of dependence and withdrawal. It is critical to ascertain whether the timing of functional or molecular changes in GABAA or NMDA receptors are associated with physiological manifestations of dependence and withdrawal, including the influence of differing endogenous regulation. These investigations are important for understanding the neurobiological basis of ethanol dependence and withdrawal in both males and females.

本提案的目标是描述乙醇依赖性性别差异的分子基础。 目的是检验性别影响慢性乙醇暴露引起的GABA和γ-氨基丁酸能系统的神经适应性的假设。 GABAA和NMDA受体是大脑中介导乙醇作用的关键部位。 乙醇依赖导致GABAA和NMDA受体基因表达和功能的亚基选择性改变。 我们最近发现，长期饮酒对GABAA受体α和NMDA NR 1亚基表达的影响存在深刻的性别差异。 这表明性别影响乙醇依赖对这两个关键神经递质系统基因表达的影响。 这表明与乙醇依赖和戒断相关的神经适应可能取决于乙醇暴露的激素背景。然而，几乎没有证据表明乙醇依赖和戒断行为与GABAA和NMDA受体的分子变化之间存在直接联系。 拟议的研究将通过将乙醇依赖的发展和恢复与基因表达和受体调节的变化相关联来研究乙醇依赖和戒断效应中性别差异的分子基础。 该提案将检验乙醇依赖诱导性别选择性改变的假设：1）GABAA受体调节、功能和基因表达，2）NMDA受体调节、功能和基因表达，3）几种关键神经活性类固醇的水平。 我们将确定这些改变是否与乙醇依赖和戒断的行为表现存在时间相关性。 这些研究特别重要，因为对慢性乙醇消耗的神经适应性表达因性别而异，即使两种性别都显示出相似的依赖和戒断行为迹象。 确定GABAA或NMDA受体的功能或分子变化的时间是否与依赖和戒断的生理表现相关，包括不同内源性调节的影响，这一点至关重要。 这些研究对于了解男性和女性酒精依赖和戒断的神经生物学基础是重要的。