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

描述（由申请人提供）：酒精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，并被列为DSM IV中酒精依赖的诊断标准之一。然而，很少有人知道的耐受性发展和酒精消费水平之间的关系，虽然有人推测，出现的耐受性乙醇的厌恶性影响可能允许更多的消费，增加酒精暴露水平和伴随的问题。探索酒精耐受性和消费之间的关系在青少年时期尤其重要，12-21岁。奥尔兹不仅每次饮酒的次数比成年人多得多，而且报告的乙醇耐受性发生率也比任何其他年龄组都高。本提案中概述的研究将使用大鼠青春期的简单且充分表征的动物模型来探索这种关系，该模型的典型特征是2-3倍高水平的乙醇消耗，表达明显更急性的耐受性（在某些情况下，慢性耐受性），并且当将处于该发育阶段的动物与成年动物进行比较时，对酒精的各种厌恶作用的敏感性减弱。拟议的工作将探讨急性和慢性耐受性的发展，乙醇的各种厌恶的影响和这些适应乙醇消费在青少年时期的关系，并在成年后可比的操作。影响这些适应的神经系统，以及这些适应是否是青春期乙醇消费量增加的原因也将进行探讨。本提案中的工作将回答以下问题：青少年和成人对乙醇的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？足以诱导对这些乙醇效应的慢性耐受性的慢性暴露方案是否会导致笼舍和限制进入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春期尤为明显（Sp. Aim 2）？NMDA和阿片受体子系统在青春期乙醇急性和慢性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是青春期乙醇消费量增加的原因？拟议的工作不仅将提供令人信服的证据，是否出现慢性耐受乙醇导致其消费量的增加，但也将阐明急性，快速和慢性耐受性之间的关系，以及耐受性发展的作用，有助于提高乙醇消费量和不敏感性的各种不良影响的乙醇特征的青春期。 公共卫生相关性：酒精耐受性的发展被认为是酒精参与问题的标志，也是用于诊断酒精依赖的标准之一，但很少有人知道耐受性发展和酒精消费水平之间的关系。探索宽容/消费关系在青春期尤为重要，因为12-21岁。奥尔兹不仅每次饮酒的次数比成年人多得多，而且他们报告的酒精耐受发生率也比任何其他年龄组都高。本提案中概述的研究将使用大鼠青春期的简单且特征良好的动物模型来比较不同形式的耐受性以及它们如何在发育过程中发生变化，探索这些酒精适应的神经基础，并确定耐受性发展是否是诱发青春期高水平酒精消费特征的原因。

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.