Stress, Rearing, and Ethanol Reinforcement in Monkeys

描述(申请人提供)：酗酒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，并造成数十亿美元的损失。酒精中毒动物模型的建立将对了解导致酒精中毒发生的生物学因素起到重要作用，并为酒精中毒的治疗提供新的药物试验手段。NIAAA临床研究实验室开发了一种非人类的灵长类酒精中毒模型，在该模型中，动物接受三种不同的饲养操作之一，旨在使它们暴露在不同程度的早期生活压力中。当几年后进行测试时，观察到口服乙醇自我给药行为的显著组间差异。本应用的第一个目的是通过测量HPA轴对α2肾上腺素能拮抗剂育亨宾、混合5-羟色胺激动剂mCPP、苯二氮卓类受体反向激动剂β-Caroline-3-羧酸乙酯和假定的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)中的八只猴子生成详细的神经内分泌学概况。第二个目的是通过检查动物在静脉注射乙醇强化的累进比率计划中的坚持程度，量化个体和群体在静脉注射乙醇自我给药动机方面的差异。第三个目的是确定实验1中给予的药理应激源对静脉注射乙醇自我给药作为预处理时的累进比率表现是否存在个体和/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，这是开发有效的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.