Effects of Acute and Chronic Alcohol on Brain Reward in Mice

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，始于最初酒精使用的愉悦和回报效果。尽管许多重叠的大脑机制有助于成瘾，但奖励和动机机制是所有成瘾性或强迫性疾病中最突出的目标。为了更好地了解过量饮酒的动机，从而制定更有效的干预策略，更彻底地了解酒精与生物奖励机制之间的关系是很重要的。该建议将重点放在酒精在小鼠模型中的奖励特性上。颅内自我刺激（ICSS）是一种用于动物研究的行为方法，对我们对可卡因、安非他明、阿片类药物和尼古丁奖励的理解做出了重大贡献。然而，ICSS在酒精奖励研究中的应用相对有限，酒精对脑刺激奖励（BSR）的影响尚未在更容易评估遗传差异的小鼠模型中进行研究。在其他操作行为方法中，动物必须执行一项任务才能获得药物强化物（动作->结果），而ICSS的主要优势在于，药物的奖励效果是独立于动物寻找或消耗药物的动机来测量的。在啮齿类动物模型中，酒精自我给药可能会因诸如味觉厌恶和口渴等因素而变得复杂，这使得研究酒精奖励的遗传和药理学调节成为一种独特而新颖的方法。我们实验室的初步研究表明，在C57BL6/J和DBA/2小鼠急性灌胃后，酒精增强了BSR的奖励价值。遗传因素约占酒精依赖风险的一半，我们的初步数据已经确定了这两种小鼠品系在酒精奖励方面的明显遗传差异：在C57BL6/J小鼠（一种自愿饮酒的品系）中，酒精剂量低于1 g/kg会增强BSR，而高于1 g/kg会降低BSR。相比之下，DBA/2小鼠在剂量高达2.4 g/kg时，BSR表现出强劲的剂量依赖性增强，但不会自愿饮酒。酒精的奖励效果在早期时间点（15-30分钟）是最大的，并且与两种品系口服后血液酒精浓度（BAC）的峰值一致，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奖励的观点。为进一步阐明急性酒精给药的药代动力学和药理作用，拟进行实验；研究间歇性或慢性酒精暴露对酒精奖励的适应性；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澄清增加饮酒倾向的机制，并通过改变酒精奖励来改变消费的新治疗靶点。

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.