The role of amygdalar estrogen receptors in ethanol reward and binge drinking

杏仁核雌激素受体在乙醇奖励和暴饮中的作用

• 批准号: 9121716
• 负责人: Elisa R. Hilderbrand
• 金额: $ 3.97万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2018-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121716
• 关键词: Accounting; Affect; Agonist; Alcohol abuse; Alcohol consumption; American; Amygdaloid structure; Animal Model; Animals; Behavior; Behavioral; Biological; Blood; Brain; Brain region; Cardiovascular system; Cell Nucleus; Cell membrane; Central Medial Thalamic Nucleus; Cessation of life; Dependence; Development; Disease; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Ethanol; Ethanol dependence; Female; Future; Gene Expression; Gene Expression Regulation; Genes; Genomics; Health; Hour; Light; Measures; Medial; Mediating; Mediator of activation protein; Messenger RNA; Molecular; Mus; Neurologic; Operative Surgical Procedures; Ovarian; Ovarian Steroid Hormone; Polymerase Chain Reaction; Population; Prevalence; Property; Protocols documentation; RNA Interference; Receptor Activation; Recovery; Research; Research Training; Rewards; Risk; Risk Factors; Role; Sex Characteristics; Steroids; Subfamily lentivirinae; Techniques; Therapeutic; Time; Tissues; United States; Woman; Women' s Health; alcohol behavior; alcohol effect; alcohol exposure; alcohol research; alcohol response; alcohol reward; alcohol use disorder; alcoholism therapy; base; behavioral response; binge drinking; brain tissue; career; conditioning; density; drinking; drinking behavior; economic cost; estrogenic; experience; knock-down; liver injury; male; men; neuromechanism; neurotransmission; pleasure; preference; public health relevance; research study; small hairpin RNA; social; therapeutic target; treatment response; treatment strategy

 DESCRIPTION (provided by applicant): Alcohol use disorders (AUDs) affect millions of Americans every year, at great personal, social, and economic cost. Women are particularly vulnerable to the negative health consequences of alcohol abuse, suffering neurological, cardiovascular, and liver damage at lower levels of alcohol abuse than men. Alarmingly, recent decades have seen a dramatic increase in the prevalence AUDs among the female population. Current treatment strategies are based on studies conducted predominantly in male animals, and little is known about sex differences in the brain's response to ethanol. A growing body of evidence suggests that estrogen receptors (ERs) are able to increase both the consumption of alcohol and the subjective pleasure (or "reward") of the alcohol experience in female animals. In preliminary studies, our lab has demonstrated increased ethanol reward and binge-like drinking behavior in female mice treated with the ovarian steroid hormone estradiol. The amygdala, a brain region well established as a mediator of AUD development in animal models of ethanol addiction, expresses a high density of ERs. Furthermore, ERs regulate the expression of multiple genes that are known modulate the effects of alcohol on amygdalar neurotransmission. The objectives of this project are therefore: 1) Determine which of the classical ERs, ERα or ERβ, is primarily responsible for estrogenic enhancement of ethanol reward and binge-like drinking behavior, 2) Investigate the effects of estrogen and ethanol on gene expression in the amygdala, and 3) Identify regions of the amygdala where ERs act to enhance ethanol-related behaviors in female mice. First, systemic treatment with the ERα- and ERβ-specific agonists PPT and DPN will be used to determine which ER mediates estradiol's enhancement of ethanol reward and binge-like drinking behavior in the conditioned place preference (CPP) and drinking in the dark (DID) paradigms, respectively. Second, amygdalar tissue will be isolated from female mice treated with ER agonists and subjected to binge ethanol exposure in the DID paradigm, and real-time polymerase chain reaction (RT-PCR) analysis will measure the expression of key genes in subregions known to be involved in behavioral responses to ethanol. Third, RNAi knockdown of ERα or ERβ expression in the central and medial amygdalar nuclei (CeA and MeA) will be used to localize ER effects on ethanol-related behaviors in naturally cycling female mice. The proposed project implements well-established behavioral and molecular techniques to investigate the role of amygdalar ERs in regulating the female brain's response to ethanol. This Research Training Plan will therefore make an important contribution to scientific understanding of AUD development in women while preparing the applicant for a successful academic career in ethanol research.

 描述(由申请人提供)：酒精使用障碍(AUD)每年影响数百万美国人，造成巨大的个人、社会和经济损失。女性尤其容易受到酒精滥用的负面健康后果的影响，与男性相比，女性在酒精滥用水平较低的情况下遭受神经、心血管和肝脏损害。令人震惊的是，近几十年来，AUDS在女性人群中的患病率急剧上升。目前的治疗策略主要是基于在雄性动物身上进行的研究，对大脑对乙醇反应的性别差异知之甚少。越来越多的证据表明，雌激素受体(ER)能够增加雌性动物的酒精消耗量和酒精体验的主观快感(或“奖励”)。在初步研究中，我们的实验室已经证明，用卵巢类固醇激素雌二醇治疗的雌性小鼠，酒精奖赏和酗酒行为增加。杏仁核是酒精成瘾动物模型中被公认为AUD发育中介的大脑区域，表达高密度的ER。此外，内质网调节多个已知的基因的表达，这些基因调节酒精对杏仁核神经传递的影响。因此，该项目的目标是：1)确定哪种经典的雌激素受体，ERα或ERβ，主要负责雌激素样增强酒精奖赏和酗酒行为；2)研究雌激素和乙醇对杏仁核基因表达的影响；3)确定杏仁核中雌激素受体促进雌性小鼠酒精相关行为的区域。首先，用ERα和ERβ特异性激动剂PPT和DPN进行系统治疗，以确定哪种ER分别介导了雌激素在条件性位置偏爱(CPP)和黑暗中饮酒(DID)范式中增强乙醇奖赏和酗酒行为。其次，杏仁核组织将从接受ER激动剂处理的雌性小鼠中分离出来，并在DID范例中接受狂欢酒精暴露，实时聚合酶链式反应(RT-PCR)分析将测量已知的与酒精行为反应相关的亚区关键基因的表达。第三，在杏仁中央和内侧核(CEA和MEA)中，ERα或ERβ表达的RNA干扰将被用来定位ER对自然循环雌性小鼠酒精相关行为的影响。这项拟议的项目采用了成熟的行为和分子技术来研究杏仁核ER在调节女性大脑对酒精的反应中所起的作用。因此，这项研究培训计划将对科学理解妇女的AUD发展作出重要贡献，同时为申请者在乙醇研究领域的成功学术生涯做好准备。