Neurobehavioral Assessment of Ethanol Seeking and Intake in the Rat

描述(由申请人提供)：酒精在人类和大鼠体内起着强有力的增强剂的作用，直接涉及酒精使用的行为可以被认为是“目标导向的”，包括两个不同的阶段：1)寻求或获得特定资源(食欲行为)，2)与该资源的实际直接互动(消耗性行为)。该项目利用了一种创新的行为模型，将获得酒精所需的初始行为与实际的酒精自我给药分开。在这个模型中，大鼠在6分钟内喝下1.0g/kg的酒精，产生药理上相关的血液酒精浓度(40-90 mg%)。此外，我们已经证明，这个模型可以识别特定影响行为的寻求或饮酒部分的药物，而对酒精动机反应的其他部分几乎没有影响。因此，这种方法提供了一个独特的机会来检查独立和/或协同影响酒精饮料的寻求和消费的因素。这项拟议的研究系统地灭活了与酒精寻求和摄入有关的极其局部的神经解剖结构，然后操纵这些区域内特定的神经化学功能，以剖析酒精动机行为背后的神经回路和神经化学。总体而言，该项目将：1)在寻找药物的研究主要集中在其他滥用药物的地方，评估以酒精为动机的行为；2)专注于相对离散的大脑结构，在这些结构中，许多方法需要较少的解剖学特异性；3)检查酒精和蔗糖强化的反应，以解释美味的卡路里目标物质共同的行为调节；4)为将酗酒的检查扩展到酒精依赖的研究奠定基础；以及5)从程序上将寻求酒精与饮酒分开，试图确定这些行为特有的和共同的神经解剖学和神经化学底物。这个项目的发现将使我们对酒精激励行为背后的神经回路有基本的理解，并确定这是一种常见的强化/成瘾回路，还是有别于酒精强化。重要的是，这些发现还将为未来的药物治疗开发奠定基础，该药物治疗可以针对个人在开始饮酒时寻求/开始饮酒和/或未能控制饮酒的特定失调。

DESCRIPTION (provided by applicant): Alcohol acts as a potent reinforcer in humans and in rats, and the behaviors directly involved in alcohol use can be thought of as "goal-directed", involving two distinct phases: 1) the seeking or procurement of a particular resource (appetitive behaviors), and 2) the actual direct interactions with that resource (consummatory behaviors). This project utilizes an innovative behavioral model developed to separate the initial behavior required to obtain access to alcohol from the actual alcohol self-administration. Using this model, rats drink alcohol in the 1.0 g/kg range in <6 minutes, producing pharmacologically relevant blood alcohol concentrations (40-90mg%). Moreover, we have demonstrated that this model can identify drugs that specifically affect either the seeking or the drinking component of behavior while having little to no effect on the other component of alcohol-motivated responding. Thus, this approach provides a unique opportunity to examine the factors that independently and/or cooperatively affect the seeking and consumption of alcoholic beverages. The proposed studies systematically inactivate extremely localized neuroanatomical structures postulated to be involved in alcohol-seeking and intake, and then manipulate specific neurochemical function within these regions to dissect the neurocircuitry and neurochemistry underlying alcohol-motivated behavior. Overall, the project will: 1) assess alcohol-motivated behaviors where the preponderance of research on drug-seeking has been on other drugs of abuse; 2) focus on relatively discrete brain structures where many approaches necessitate less anatomical specificity; 3) examine alcohol vs. sucrose-reinforced responding to account for the regulation of behavior that is common to palatable, caloric goal substances; 4) lay the groundwork for the extension of the examination of binge drinking to the study of alcohol dependence; and 5) procedurally separate alcohol-seeking from drinking to attempt to identify the neuroanatomical and neurochemical substrates specific and common to these behaviors. The findings from this project will inform our basic understanding of the neural circuitry underlying alcohol-motivated behavior and determine whether or not this is a common reinforcement/addiction circuit or distinct to alcohol reinforcement. Importantly, these findings will also lay the groundwork for future pharmacotherapy development that can target an individual's specific dysregulation of seeking/initiation of drinking and/or failure to control drinking once begun.