Acute and Chronic Tolerance to Ethanol in Adolescence: Impact on Consumption

项目总结/摘要 对酒精的耐受性的发展被认为反映了有问题的酒精参与的关键标志， 在DSM IV中被列为酒精依赖的诊断标准之一。但人们对它知之甚少。 耐受性发展和酒精消费水平之间的关系，尽管它一直是 据推测，对乙醇的厌恶作用的耐受性的出现可能允许更多的消费， 增加酒精暴露水平和伴随的问题。探索乙醇与 在青春期，12-21岁的人的耐受性和消费能力尤其重要。奥尔兹不仅喝酒 每次饮酒的次数比成年人多得多，但也报告了更高的乙醇耐受性发生率 比任何其他年龄组。本提案中概述的研究将使用一个简单的 在大鼠中的青春期的良好表征的动物模型，该模型的典型特征是2-3倍高水平的 乙醇消耗，表现出明显更急性的耐受性（在某些情况下，慢性耐受性）， 耐受性），以及对酒精的各种厌恶作用的敏感性减弱，当动物处于这种状态时， 发育阶段与成人相比。拟议的工作将探讨急性和 对乙醇各种不良影响的慢性耐受性以及这些适应与乙醇的关系 在青少年时期和成年期进行类似的操作后，神经 影响这些适应的系统，以及这些适应是否是乙醇浓度升高的原因 此外，亦会探讨青少年的消费情况。本提案中的工作将回答以下问题 问题：急性，快速和慢性耐受性的出现之间的关系是什么？ 乙醇对青少年和成人的厌恶作用（Sp.Aim 1）？慢性接触方案是否足以 诱导对这些乙醇作用慢性耐受性导致家庭中自愿乙醇消耗的增加 笼式和限制进入试验，这种增加的消费在青春期特别明显 （目标2）？NMDA和阿片受体亚系统在急性和慢性脑缺血的发生中起什么作用？ 在青春期对乙醇的耐受性（目标3）？最后，适应性变化是否与 慢性耐受性发展是青春期乙醇消耗量增加的原因（目标4）？的 拟议的工作不仅将提供令人信服的证据，以证明是否出现慢性耐受， 乙醇导致其消费量增加，但也将阐明急性，快速和 慢性耐受性和耐受性发展在促进乙醇消耗量升高中的作用 以及青春期特有的对酒精的各种厌恶作用的不敏感。

PROJECT SUMMARY/ABSTRACT Development of tolerance to alcohol is thought to reflect a critical sign of problematic alcohol involvement, and is included as one of the diagnostic criteria for alcohol dependence in the DSM IV. Yet little is known of the relationship between tolerance development and levels of alcohol consumption, although it has been speculated that emergence of tolerance to aversive effects of ethanol may permit greater consumption, increasing alcohol exposure levels and concomitant problems. Exploring the relationship between ethanol tolerance and consumption is particularly critical during adolescence, with 12-21 yr. olds not only drinking substantially more per drinking occasion than adults, but also reporting a higher incidence of ethanol tolerance than any other age group. The studies outlined in this proposal will explore this relationship using a simple and well characterized animal model of adolescence in the rat, a model that is typified by 2-3 fold high levels of ethanol consumption, expression of markedly more acute tolerance (and under some instances, chronic tolerance), and an attenuated sensitivity to various aversive effects of alcohol when animals in this developmental phase are compared with adults. The proposed work will explore the development of acute and chronic tolerance to various aversive effects of ethanol and the relationships of these adaptations to ethanol consumption during the adolescent period and following comparable manipulations in adulthood. Neural systems influencing these adaptations and whether these adaptations are causal for elevated ethanol consumption during adolescence will also be explored. Work in this proposal will answer the following questions: What are the relationships among the emergence of acute, rapid and chronic tolerance for various aversive effects of ethanol in adolescents and adults (Sp.Aim 1)? Do chronic exposure regimens sufficient to induce chronic tolerance to these ethanol effects lead to increases in voluntary ethanol consumption in home cage and limited access tests, with this increased consumption being particularly marked in adolescence (Sp.Aim 2)? What role do NMDA and opioid receptor subsystems play in the emergence of acute and chronic tolerance to ethanol during adolescence (Sp.Aim 3)? And, finally, are the adaptive changes associated with chronic tolerance development causal for increasing ethanol consumption in adolescence (Sp.Aim 4)? The proposed work will not only provide convincing evidence as to whether the emergence of chronic tolerance to ethanol leads to increases in its consumption, but will also illuminate the relationships among acute, rapid and chronic tolerance and the role of tolerance development in contributing to the elevated ethanol consumption and the insensitivity to various aversive effects of ethanol characteristic of adolescence.