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

描述（由申请人提供）：对酒精的耐受性的发展被认为反映了问题酒精参与的一个关键标志，并被列入DSM IV中作为酒精依赖的诊断标准之一。然而，对耐受性发展与酒精消费水平之间的关系知之甚少，尽管有人推测，对乙醇的不良影响的耐受性的出现可能会允许更大的消费，增加酒精暴露水平和伴随的问题。探索乙醇耐受性和酒精消费量之间的关系在青春期尤为重要，12-21岁的青少年不仅每次饮酒的饮酒量比成年人多得多，而且报告的乙醇耐受性发生率也高于其他任何年龄组。本提案中概述的研究将使用一个简单且具有良好特征的大鼠青春期动物模型来探索这种关系，该模型的典型特征是乙醇消耗量高2-3倍，表现出明显更多的急性耐受性（在某些情况下，慢性耐受性），并且在此发育阶段的动物与成年动物相比，对酒精的各种不良影响的敏感性减弱。提出的工作将探讨急性和慢性对乙醇的各种不良影响的耐受性的发展，以及这些适应在青春期和成年期对乙醇消费的关系。影响这些适应的神经系统，以及这些适应是否是青春期酒精消耗量增加的原因，也将被探讨。本提案的工作将回答以下问题：青少年和成人对乙醇各种不良影响的急性、快速和慢性耐受性的出现之间有什么关系（Sp. Aim 1）？长期暴露方案是否足以诱导对这些乙醇效应的慢性耐受性，从而导致家庭笼试验和有限接触试验中自愿乙醇消耗量的增加，并且这种增加的消耗量在青少年中尤其明显（Sp.目标2）？NMDA和阿片受体子系统在青春期急性和慢性乙醇耐受性的出现中起什么作用？最后，与慢性耐受性发展相关的适应性变化是否导致了青春期乙醇消耗量的增加（Sp. Aim 4）？本研究不仅为慢性乙醇耐受性的出现是否会导致乙醇消耗量的增加提供了令人信服的证据，而且还将阐明急性、快速和慢性耐受性之间的关系，以及耐受性发展在促进乙醇消耗量增加和青少年对乙醇的各种厌恶效应不敏感方面的作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Development of alcohol tolerance is viewed as a sign of problematic alcohol involvement and is one of the criteria used to diagnose alcohol dependence, yet little is know of the relationship between tolerance development and levels of alcohol consumption. Exploring tolerance/consumption relationships is particularly critical during adolescence, given that 12-21 yr. olds not only drink substantially more per drinking occasion than adults, but they also report a higher incidence of alcohol tolerance than any other age group. The studies outlined in this proposal will use a simple and well-characterized animal model of adolescence in the rat to compare different forms of tolerance and how they change developmentally, explore the neural substrates of these adaptations to alcohol, and determine whether tolerance development is causal for inducing the high levels of alcohol consumption characteristic of the adolescent period.