Drug Treatment of Ethanol Seeking in Rat and Monkey

描述（由申请人提供）： 为了确定可能有效减少乙醇滥用的药物，对乙醇具有特异性，并且不会改变由其他强化物质引起的行为，需要接近人类状况的动物模型。该项目提出了一个操作性的行为模式，允许乙醇自我管理的相关水平，程序上分离的寻求酒精饮料，并使用两种动物（大鼠和猴子）在不同阶段的乙醇经验。经验将从单一的每日饮酒回合（大鼠），滥用消费（猴子），乙醇依赖（大鼠）。该项目的总体目标是开发和扩展行为范式，分别测量寻求酒精和酒精消费，以测试跨物种研究治疗酒精滥用的假定药物疗法。将使用三种方法：1）非依赖性大鼠，每天有限地接触蔗糖或乙醇，2）乙醇依赖性大鼠在吸入蒸汽室中产生依赖性并在操作室中进行测试，3）重度乙醇饮用猴，每天延长乙醇接触时间。将通过使用甜味液体作为药物对其他类型的饮酒动机行为的影响的对照，确定乙醇的选择性。此外，由于GABA（A）系统与乙醇的强化和行为效应有关，因此将在该模型中测试GABA（A）受体配体。将GABA（A）调节作用的概况与两种当前药物疗法（纳洛酮和阿坎酸）的作用进行比较。“成功的药物治疗”将减少乙醇寻求行为，并且将对乙醇具有选择性，对对照液的增强反应几乎没有影响。总体而言，该项目允许在接受类似治疗的依赖性和非依赖性受试者之间进行比较，并在一个实验室中对大鼠和猴子进行比较。该项目回应了RFA要求的5个感兴趣领域中的3个：测试具有已知药理学特性的药物的治疗效果，开发具有高预测有效性的新动物模型，以及进一步研究目前用于治疗酒精滥用的药物。

DESCRIPTION (provided by applicant): To identify drugs that are likely to be efficacious at decreasing ethanol abuse, are specific to ethanol, and do not alter behaviors motivated by other reinforcing substances, animal models that closely approximate the human condition are necessary. This project proposes the use of an operant behavioral paradigm that allows for pharmacologically relevant levels of ethanol self-administration, that procedurally separates reinforcer-seeking from reinforcer drinking, and that uses two species of animals (rats and monkeys) in varying stages of ethanol experience. Experience will range from single daily drinking bouts (rats), to abusive consumption (monkeys), to ethanol-dependence (rats). The overall goal of this project is to develop and expand the behavioral paradigm that separately measures reinforcer-seeking and reinforcer consumption to test putative pharmacotherapies for the treatment of alcohol abuse with across-species studies. Three approaches will be utilized: 1) nondependent rats with daily, limited access to sucrose or ethanol, 2) ethanol-dependent rats made dependent in inhalation vapor chambers and tested in operant chambers, and 3) heavy ethanol-drinking monkeys with extended daily access to ethanol. Selectivity for ethanol will be determined by using a sweetened fluid as a control for drug effects on other types of reinforcer-motivated behaviors. Also, since the GABA(A) system has been implicated in the reinforcing and behavioral effects of ethanol, GABA(A) receptor ligands will be tested in this model. The profile of GABA(A) modulatory effects will be compared to the effects of two current pharmacotherapies (naltrexone and acamprosate). A "successful pharmacotherapy" will decrease ethanol-seeking behavior and will be selective for ethanol with little to no effect on reinforced responding for the control fluid. Overall, the project allows for the comparison between dependent and nondependent subjects undergoing similar treatments, and the comparison between rats and monkeys in one laboratory. This project responds to 3 of the 5 areas of interest requested in the RFA: testing drugs with known pharmacological properties for therapeutic efficacy, developing a new animal model with high predictive validity, and further research on drugs currently used for the treatment of alcohol abuse.