Effects of Acute and Chronic Alcohol on Brain Reward in Mice

急性和慢性酒精对小鼠大脑奖赏的影响

• 批准号: 8215758
• 负责人: C J MALANGA
• 金额: $ 33.68万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215758
• 关键词: Acute; Address; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Beverages; Alcoholism; Alcohols; American; Americas; Amphetamines; Animals; Behavior; Behavioral; Biological; Blood alcohol level measurement; Brain; Chemosensitization; Chronic; Cocaine; Complex; Consumption; DBA/2 Mouse; Data; Development; Dietary Alcohol; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopaminergic Agents; Dose; Drug Kinetics; Genetic; Heavy Drinking; Impairment; Inbred Strains Mice; Intervention; Laboratories; Lead; Measures; Mediating; Methods; Motivation; Mouse Strains; Mus; Nicotine; Opiates; Oral; Oral Administration; Outcome; Pain; Pathway interactions; Pharmaceutical Preparations; Phase; Property; Public Health; Regulation; Rewards; Risk; Rodent Model; Role; Science; Self Administration; Self Stimulation; Self-Administered; Signal Transduction; System; Taste Perception; Testing; Thirst; Time; Translating; United States; Withdrawal; addiction; alcohol effect; alcohol exposure; alcohol reward; alcohol sensitivity; alcohol use disorder; base; cost; drinking; effective therapy; falls; genetic strain; insight; mouse model; neural circuit; new therapeutic target; novel strategies; public health relevance; receptor; reinforcer; research study; social; sound

DESCRIPTION (provided by applicant): Alcohol use disorders and alcoholism are complex behavioral and biological endpoints that begin with the pleasurable, rewarding effects of initial alcohol use. Although many overlapping brain mechanisms contribute to addiction, mechanisms of reward and motivation are among the most salient targets of all addictive or compulsive disorders. To better understand what motivates excessive alcohol consumption, and thereby develop more effective strategies for intervention, a more thorough understanding of the relationship between alcohol and biological mechanisms of reward is important. This proposal will focus on the rewarding properties of alcohol in mouse models. Intracranial self-stimulation (ICSS) is a behavioral method used in animal studies that has made major contributions to our understanding of cocaine, amphetamine, opiate and nicotine reward. However, the application of ICSS to the study of alcohol reward has been comparatively limited, and the effects of alcohol on brain stimulation-reward (BSR) have not been studied in mouse models where genetic differences can more easily be evaluated. The main advantage of ICSS over other operant behavioral methods in which the animal must perform a task in order to receive a drug reinforcer (action->outcome) is that the rewarding effect of a drug is measured independent of the motivation of the animal to seek or consume the drug. Alcohol self-administration in rodent models may be complicated by factors such as taste aversion and thirst that are avoided with ICSS, which allows a unique and novel approach to investigate the genetic and pharmacological regulation of alcohol reward. Preliminary studies in our laboratory have shown that alcohol potentiates the rewarding value of BSR after acute administration by oral gavage in both C57BL6/J and DBA/2 mice. Genetic factors represent about half of the risk for alcohol dependence, and our preliminary data have established clear genetic differences in alcohol reward between these two mouse strains: alcohol doses lower than 1 g/kg potentiate BSR while doses higher than 1 g/kg depreciate BSR in C57BL6/J mice, a strain that voluntarily consumes alcohol. In contrast, DBA/2 mice show a robust, dose-dependent potentiation of BSR at doses up to 2.4 g/kg but do not voluntarily consume alcohol. The rewarding effect of alcohol is greatest at early time points (15-30 minutes) and coincides with the peak blood alcohol concentration (BAC) after oral administration in both strains, supporting the idea that animals find the rising phase of the BAC curve more pleasurable or rewarding than the falling phase. Experiments are proposed to further elucidate the pharmacokinetics and pharmacological effects of acute alcohol administration; to investigate adaptations to alcohol reward with intermittent or chronic alcohol exposure; and to determine the contribution of dopaminergic mechanisms to alcohol reward. Understanding the role of reward in alcohol dependence will clarify mechanisms of increased drinking liability and lead to insights into novel therapeutic targets that modify consumption by changing alcohol reward. PUBLIC HEALTH RELEVANCE: The behavioral and biological problems of alcohol abuse begin with the pleasurable or rewarding effects of alcohol use. Alcohol use disorders are a major public health problem, costing American taxpayers almost $200 billion each year. The development of new and effective treatments based on sound neuroscientific evidence is critical to address the pain and impairment these disorders bring to the nearly 10 million people who suffer from them in the United States of America.

描述(申请人提供)：酒精使用障碍和酒精中毒是复杂的行为和生物终点，始于首次饮酒带来的愉快和有益的影响。尽管许多相互重叠的大脑机制导致上瘾，但奖励和动机机制是所有成瘾性或强迫症最显著的目标之一。为了更好地了解过度饮酒的动机，从而制定更有效的干预策略，更彻底地了解酒精与奖赏的生物机制之间的关系是重要的。该提案将重点放在酒精在小鼠模型中的有益特性上。颅内自我刺激(ICSS)是一种用于动物研究的行为学方法，它为我们理解可卡因、安非他明、阿片剂和尼古丁奖赏做出了重要贡献。然而，ICSS在酒精奖赏研究中的应用相对有限，在更容易评估遗传差异的小鼠模型中，还没有人研究酒精对脑刺激-奖赏(BSR)的影响。与动物必须完成一项任务以获得药物增强剂(作用结果)的其他可操作行为方法相比，ICSS的主要优势是药物的奖励效应是独立于动物寻求或消费药物的动机来衡量的。在啮齿动物模型中，酒精自我给药可能会因味道厌恶和口渴等因素而变得复杂，而ICSS可以避免这些因素，这为研究酒精奖励的遗传和药物调节提供了一种独特的新方法。我们实验室的初步研究表明，在C57BL6/J和DBA/2小鼠中，酒精都能增强急性灌胃给药后BSR的奖赏价值。遗传因素约占酒精依赖风险的一半，我们的初步数据已经在这两个小鼠品系之间建立了明显的酒精奖励遗传差异：低于1g/kg的酒精剂量会增强C57BL6/J小鼠的BSR，而高于1g/kg的剂量会降低BSR，C57BL6/J小鼠是一种自愿饮酒的品系。相比之下，DBA/2小鼠在剂量高达2.4g/kg时表现出强烈的、剂量依赖的BSR增强，但不自愿饮酒。酒精的奖励效应在早期时间点(15-30分钟)最大，与两个品系口服后的血液酒精浓度(BAC)峰值一致，支持动物认为BAC曲线的上升阶段比下降阶段更令人愉快或更有回报的观点。拟通过实验进一步阐明急性酒精给药的药代动力学和药理学效应；研究间歇或慢性酒精暴露对酒精奖赏的适应性；以及确定多巴胺能机制对酒精奖赏的贡献。了解奖赏在酒精依赖中的作用将澄清饮酒倾向增加的机制，并导致对通过改变酒精奖赏来改变消费的新治疗靶点的洞察。 与公共健康相关：酗酒的行为和生物问题始于饮酒的愉悦或有益效果。酒精使用障碍是一个主要的公共卫生问题，每年给美国纳税人造成近2000亿美元的损失。根据可靠的神经科学证据开发新的有效治疗方法，对于解决这些疾病给美利坚合众国近1000万人带来的痛苦和损害至关重要。