Stress, Rearing, and Ethanol Reinforcement in Monkeys

描述（由申请人提供）：酗酒是美国一个主要的公共卫生问题，每年导致成千上万的美国人死亡，造成数十亿美元的损失。酒精中毒动物模型的建立将在理解导致酒精中毒的生物学因素方面发挥重要作用，并为测试治疗酒精中毒的新药物提供一种手段。NIAAA的临床研究实验室开发了一种非人类灵长类动物酒精中毒模型，在该模型中，动物受到三种不同饲养方法中的一种，这些方法旨在使它们暴露在不同程度的早期生活压力下。几年后进行测试时，观察到口服乙醇自我给药行为的显著组间差异。当前应用程序的第一个目标是通过测量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、苯二氮卓受体逆激动剂-碳-3-羧酸乙酯和推测的CRHR1受体激动剂EG1的剂量效应和时间过程，为三个饲养组（n=24）中的每组8只猴子生成详细的神经内分泌学特征。第二个目标是量化个体和群体之间的差异，在他们的动机，静脉注射自我管理乙醇通过检查程度，他们坚持一个渐进的比例计划静脉注射乙醇强化。第三个目的是确定实验1中给药的药理学应激源对静脉注射乙醇自我给药的递进比表现的影响是否存在个体和/或群体差异。这些研究将有助于更好地了解酒精中毒的生物学基础，这是开发有效药物治疗干预措施的第一步。

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.