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

描述(由申请人提供)：酒精耐受性的形成被认为反映了有问题的酒精参与的关键迹象，并被列为DSM IV中酒精依赖的诊断标准之一。然而，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，对酒精的不良影响出现耐受性可能会导致更多的饮酒，增加酒精暴露水平和伴随的问题。在12-21岁的青春期，探索酒精耐量和饮酒之间的关系尤其关键。老年人不仅每次饮酒的次数比成年人多得多，而且报告的酒精耐受率也高于其他任何年龄段。这项建议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酒精消耗量高出2-3倍，表现出明显更急性的耐受性(在某些情况下，还有慢性耐受性)，以及当与成年动物相比时，对酒精的各种厌恶效应的敏感性减弱。这项拟议的工作将探索对乙醇的各种不良影响的急性和慢性耐受性的发展，以及这些适应与青春期和成年后类似操作的酒精消费的关系。还将探索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摄入量增加的原因。这项提案中的工作将回答以下问题：在青少年和成年人中出现对酒精的各种厌恶影响的急性、快速和慢性耐受性之间有什么关系(Sp。目标1)？慢性暴露疗法是否足以诱导对这些乙醇效应的慢性耐受，从而导致家庭笼子中自愿的乙醇消费增加和有限的接触试验，这种增加的消费在青春期尤为明显(SP。目标2)？NMDA和阿片受体亚系统在青春期对乙醇的急性和慢性耐受性的出现中发挥了什么作用(SP。目标3)？最后，与慢性耐受发展相关的适应性变化是青春期酒精摄入量增加的原因(SP。目标4)？这项拟议的工作不仅将提供令人信服的证据，证明慢性乙醇耐受性的出现是否会导致乙醇消费量的增加，而且还将阐明急性、快速和慢性耐受性之间的关系，以及耐受性发展在导致酒精消耗量增加以及青少年对酒精的各种厌恶效应不敏感方面所起的作用。 公共卫生相关性：酒精耐受性的发展被视为有问题的酒精参与的迹象，也是用于诊断酒精依赖的标准之一，但人们对耐受性发展和酒精消费水平之间的关系知之甚少。考虑到12-21岁的青少年，探索容忍/消费关系在青春期尤为关键。老年人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率也高于其他任何年龄段。这项建议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比较不同形式的耐受性及其在发育过程中的变化，探索这些对酒精的适应的神经基础，并确定耐受性发展是否导致青春期特征的高水平饮酒。

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.