Alcohol Tolerance and Behavioral Disinhibition in Humans

描述（由申请方提供）：酒精耐受性是指重复给药时反应强度降低。长期以来，耐受性一直被认为是导致酒精滥用和依赖的一个因素，因为它鼓励使用逐渐增加的剂量来恢复药物的初始效果。酒精也因其对参与行为和注意力调节的神经认知过程的急性损害作用而闻名。然而，很少有研究探讨这种干扰如何降低对实际饮酒的自我控制，导致滥用饮酒的模式（例如，豪饮）。此外，尽管对耐受性作为酒精使用障碍的表型标志物感兴趣，但很少有研究试图确定酒精敏感性和耐受性的差异如何表征酒精滥用风险人群，例如患有外化障碍的人群（例如，ADHD）。该建议是基于工作的假设，即酒精的滥用潜力是由其奖励增强作用和其抑制作用的敏感性决定的。拟议中的研究检查了耐受性对滥用潜力的贡献，通过改变酒精对控制和调节行为的基本机制的影响来衡量。研究将调查：1）控制机制对酒精损害效应的敏感性及其对滥用潜力的贡献; 2）对控制行为和注意力的机制的损害效应的耐受性发展; 3）这种耐受性对酒精滥用潜力的贡献; 4）与ADHD相关的抑制和注意力缺陷影响酒精敏感性和耐受性发展的程度;和5）耐受性的发展过程受到同时使用常用于ADHD管理的刺激性药物的影响的程度。公共卫生相关性：过度饮酒会导致许多不良健康后果（例如，酒精中毒、急性酒精性肝炎和肝硬化）。长期以来，耐受性一直被认为是导致酒精滥用和依赖的一个因素，因为它鼓励使用逐渐增加的剂量来恢复药物的初始效果。然而，很少有研究探讨耐受性如何增加酗酒的风险。拟议的研究检查了耐受性对滥用潜力的贡献，通过药物改变行为控制和调节中涉及的基本机制的能力变化来衡量。这项研究的结果将提供一个了解饮酒者对酒精的急性行为损害效应的易感性如何通过促进持续的滥用狂欢饮酒模式，对后来的酒精依赖构成早发性风险因素。研究策略还将提供方法来测试神经认知机制在现有药物治疗（如纳洛酮和阿坎酸）以及一些可能通过神经认知控制机制运作的研究药物的治疗效果中的作用。

DESCRIPTION (provided by applicant): Alcohol tolerance refers to a diminished intensity of response as doses are repeated. Tolerance has long been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of the drug. Alcohol is also well-known for its acute impairing effects on neurocognitive processes involved in the regulation of behavior and attention. Yet, little research has examined how such disturbances might reduce self-control over actual alcohol use, leading to patterns of abusive drinking (e.g., binge drinking). Moreover, despite interest in tolerance as a phenotypic marker for alcohol use disorders, little research has sought to determine how differences in alcohol sensitivity and tolerance might characterize populations at-risk for alcohol abuse, such as those with externalizing disorders (e.g., ADHD). The proposal is based on the working hypothesis that abuse potential of alcohol is determined by sensitivity to its reward-enhancing effects and to its disinhibiting effects. The proposed studies examine the contribution of tolerance to abuse potential as measured by changes in alcohol effects on basic mechanisms involved in the control and regulation of behavior. Studies will investigate: 1) the sensitivity of control mechanisms to the impairing effects of alcohol and their contribution to abuse potential; 2) tolerance development to the impairing effects on mechanisms that control behavior and attention; 3) the contribution of such tolerance to the abuse potential of alcohol; 4) the degree to which the inhibitory and attentional deficits associated with ADHD influence alcohol sensitivity and the development of tolerance; and 5) the degree to which the developmental course of tolerance is affected by concomitant use of stimulant drugs commonly used in the management of ADHD. PUBLIC HEALTH RELEVANCE: Excessive alcohol use contributes to many adverse health consequences (e.g., alcohol poisoning, acute alcoholic hepatitis and liver cirrhosis). Tolerance has long been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of the drug. Yet, little research has examined how tolerance might increase the risk for alcohol abuse. The proposed studies examine the contribution of tolerance to abuse potential as measured by changes in the ability of the drug to alter basic mechanisms involved in the control and regulation of behavior. The findings of this research will provide an understanding of how drinkers' susceptibility to alcohol's acute behavioral-impairing effects can pose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking. The research strategies also will provide methods for testing the role of neurocognitive mechanisms in the treatment efficacy of existing pharmacotherapies, such as naltrexone and acamprosate, as well as some investigational medications that might operate via neurocognitive control mechanisms.