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: 8015614
• 负责人: C J MALANGA
• 金额: $ 32.37万
• 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/8015614
• 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（由申请人提供）：酒精使用障碍和酒精中毒是复杂的行为和生物学终点，始于最初的酒精饮酒的愉悦，有益的影响。尽管许多重叠的大脑机制会导致成瘾，但奖励和动机的机制是所有成瘾性或强迫性疾病中最突出的目标之一。为了更好地了解是什么激发了过度饮酒的原因，从而制定了更有效的干预策略，对酒精与奖励生物学机制之间的关系有更透彻的理解很重要。该建议将集中于小鼠模型中酒精的奖励性能。颅内自我刺激（ICS）是一种在动物研究中使用的行为方法，它为我们对可卡因，苯丙胺，鸦片和尼古丁奖励做出了重大贡献。然而，在小鼠模型中，尚未对脑刺激奖励（BSR）进行相对有限的ICS在酒精奖励研究中的应用，并且在遗传差异更容易评估的小鼠模型中尚未研究。 ICS比其他操作行为方法的主要优点是，动物必须执行任务才能接受药物增强剂（动作 - >结果）的主要优势在于，药物的奖励作用是独立于动物寻求或消费药物的动机的测量。啮齿动物模型中的酒精自我给药可能会因避免使用ICS避免的口味和口渴等因素而变得复杂，这允许一种独特而新颖的方法来研究酒精奖励的遗传和药理调节。我们实验室的初步研究表明，酒精在C57BL6/J和DBA/2小鼠中急性施用后，酒精会增强BSR的奖励值。遗传因素约占酒精依赖风险的一半，而我们的初步数据已经确定了这两种小鼠菌株之间酒精奖励的明显遗传差异：酒精剂量低于1 g/kg的BSR，而剂量降低了1 g/kg的剂量，高于1 g/kg的剂量在C57BL6/j小鼠中贬低了BSR，这是一种自愿消耗酒精的菌株。相比之下，DBA/2小鼠以剂量为2.4 g/kg的BSR表现出强大的剂量依赖性增强，但不会自愿食用酒精。酒精的奖励作用在早期（15-30分钟）时最大，并且两种菌株口服给药后的峰值血液酒精浓度（BAC）一致，这支持了动物发现BAC曲线的上升阶段比下降阶段更令人愉悦或有益。提出了实验，以进一步阐明急性酒精给药的药代动力学和药理作用。研究间歇性或慢性酒精暴露的适应酒精奖励；并确定多巴胺能机制对酒精奖励的贡献。了解奖励在酒精依赖中的作用将阐明增加饮酒责任的机制，并导致对新型治疗靶标的深入了解，从而通过改变酒精奖励来改变消费。 公共卫生相关性：酗酒的行为和生物学问题始于酒精使用的愉悦或有意义的影响。酒精使用障碍是一个主要的公共卫生问题，每年使美国纳税人造成近20​​00亿美元的损失。基于合理的神经科学证据的新有效治疗的发展对于解决这些疾病带给美国遭受近1000万人遭受痛苦的痛苦和障碍至关重要。