Stress, Rearing, and Ethanol Reinforcement in Monkeys

描述（由申请人提供）：酒精中毒是美国的一个主要公共卫生问题，每年导致数万美国人死亡，耗资数十亿美元。酒精中毒动物模型的开发将在理解导致酒精中毒发展的生物学因素方面发挥重要作用，并提供一种测试治疗酒精中毒的新药物的方法。NIAAA的临床研究实验室已经开发出一种非人灵长类动物酒精中毒模型，其中动物受到三种不同的饲养操作之一，旨在使它们暴露于不同程度的早期生活压力。多年后进行测试时，观察到口服乙醇自我给药行为的显著组间差异。本申请的第一个目的是通过测量HPA轴对α 2肾上腺素能拮抗剂育亨宾、混合5-羟色胺激动剂mCPP、苯二氮受体反向激动剂β-咔啉-3-羧酸乙酯和假定的CRHR 1受体激动剂EG 1。第二个目的是量化个体和组之间的差异，在他们的动机静脉注射自我管理的乙醇，通过检查他们坚持静脉注射乙醇强化的渐进比例时间表的程度。第三个目的是确定是否有个体和/或组差异的影响，在实验1中给予的药理学应激对渐进比性能静脉乙醇自我管理时，作为预处理。这些研究将有助于更好地了解酒精中毒的生物学基础，这是发展有效药物干预的第一步。

DESCRIPTION (provided by applicant): Alcoholism is a major public health problem in the United States, resulting in the annual death of tens of thousands of Americans and costing billions of dollars. The development of animal models of alcoholism will play an important role in understanding the biological factors that contribute to the development of alcoholism and provide a means of testing novel medications for its treatment. A nonhuman primate model of alcoholism has been developed at the NIAAA's Laboratory of Clinical Studies in which animals are subjected to one of three different rearing manipulations that are designed to expose them to varying degrees of early life stress. When tested years later, significant group differences in oral ethanol self-administration behavior are observed. The first aim of the current application is to generate a detailed neuroendocrinological profile for eight monkeys in each of the three rearing groups (n=24) by measuring the dose-effect and time-course of the HPA axis response to the alpha 2 adrenergic antagonist yohimbine, the mixed serotonin agonist mCPP, the benzodiazepine receptor inverse agonist beta-carboline-3-carboxylic acid ethyl ester, and the putative CRHR1 receptor agonist EG1. The second aim is to quantify individual and group differences among the animals in their motivation to intravenously self-administer ethanol by examining the extent to which they persist on a progressive ratio schedule of intravenous ethanol reinforcement. The third aim is to determine whether there are individual and/or group differences in the effect that the pharmacological stressors administered in Experiment 1 have on progressive ratio performance for intravenous ethanol self-administration when given as pretreatments. These studies will contribute to a better understanding of the biological basis of alcoholism, which is a first step toward the development of effective pharmacotherapeutic interventions.