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

青春期乙醇的急性和慢性耐受性：对消费的影响

• 批准号: 7919407
• 负责人: LINDA PATIA SPEAR
• 金额: $ 33.43万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919407
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Animals; Attenuated; Body Weight; Characteristics; Chronic; Consumption; Cues; Dependence; Development; Diagnosis; Diagnostic; Diagnostic and Statistical Manual; Diagnostic and Statistical Manual of Mental Disorders; Ethanol; Genetic; Growth; Home environment; Incidence; Intake; Lead; Metabolic; Modeling; N-Methylaspartate; Opioid Receptor; Phase; Play; Rattus; Regimen; Relative (related person); Reporting; Role; Sedation procedure; System; Taste Perception; Testing; Time; Work; age group; alcohol effect; alcohol exposure; alcohol involvement; drinking; drinking behavior; indexing; public health relevance; relating to nervous system; social; twelfth grade; university student; young adult

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.

描述（由申请人提供）：认为对酒精的耐受性的发展反映了有问题的酒精参与的关键迹象，并将其作为DSM IV中酒精依赖性的诊断标准之一。然而，尽管据推测，对乙醇厌恶作用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，但知之甚少，尽管据推测，耐受性发展与饮酒水平之间的关系知之甚少。在青春期，探索乙醇耐受性和消费之间的关系尤其至关重要，而12 - 21年。老年人不仅比成年人喝酒要大得多，而且报告乙醇耐受性的发病率比任何其他年龄段都更高。该提案中概述的研究将使用大鼠青春期的简单动物模型探索这种关系，该模型由2-3倍高的乙醇消耗量高，显着表达更急性的耐受性（在某些情况下，在某些情况下，慢性耐受性），以及对各种动物相比的饮酒敏感性的敏感性。拟议中的工作将探讨乙醇对各种厌恶作用的急性和长期耐受性的发展以及这些适应对乙醇消耗的关系，并在成年后进行了可比的操作。还将探索影响这些适应性的神经系统以及这些适应性是否是为了升高青春期乙醇消耗的因果。该提案中的工作将回答以下问题：急性，快速和长期耐受性对乙醇在青少年和成年人中的各种厌恶作用之间的关系是什么（sp。AIM1）？慢性暴露方案是否足以诱导对这些乙醇作用的长期耐受性导致家居笼中自愿乙醇消耗的增加和有限的接入测试，而这种增加的消费量在青春期特别明显（sp。AIM2）？ NMDA和阿片受体子系统在青春期对乙醇的急性和慢性耐受性的出现（sp。AIM3）中起什么作用？最后，是否与慢性耐受性发展因果关系增加了青春期乙醇消耗的因果关系的自适应变化（sp。AIM4）？拟议的工作不仅将提供令人信服的证据，表明对乙醇的长期耐受性是否会导致其消费增加，而且还将阐明急性，快速和长期耐受性之间的关系，以及耐受性发展在促进乙醇消耗和对各种具有乙醇异性的厌含性的厌恶效果的作用中的作用。 公共卫生相关性：耐受性的发展被视为有问题的酒精参与的迹象，并且是用于诊断酒精依赖性的标准之一，但对耐受性发展与饮酒水平之间的关系几乎没有。考虑到12 - 21年，探索耐受性/消费关系在青春期尤为重要。老年人不仅每场饮酒时间都比成年人喝得更多，而且还报告了与其他年龄段相比，他们的酒精耐受性更高。该提案中概述的研究将在大鼠中使用青春期的简单且特征良好的动物模型比较不同形式的耐受性及其在发育方面的变化，探索这些适应性酒精的神经底物的变化，并确定耐受性发展是否是诱导青少年时期饮酒量高的原因。