Alcohol Tolerance and Behavioral Disinhibition in Humans

描述（由申请人提供）：酒精耐受性是指随着剂量的重复，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，因为它鼓励使用不断增加的剂量来恢复药物的初始效果。酒精还因其对涉及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，很少有研究调查这些干扰是如何降低实际饮酒时的自制力，从而导致滥用饮酒的模式（例如，酗酒）。此外，尽管对耐受性作为酒精使用障碍的表型标记感兴趣，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，例如外化障碍（例如ADHD）人群。这一建议是基于一种可行的假设，即酒精的滥用潜力是由对其奖励增强作用和去抑制作用的敏感性决定的。拟议的研究通过酒精对行为控制和调节所涉及的基本机制的影响变化来衡量耐受性对滥用潜力的贡献。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)对行为和注意力控制机制的损害作用的耐受性发展；3)这种耐受性对酒精滥用可能性的贡献；4)与ADHD相关的抑制和注意缺陷对酒精敏感性和耐受性发展的影响程度；5)同时使用ADHD治疗中常用的兴奋剂对耐受性发育过程的影响程度。公共卫生相关性：过度饮酒会导致许多不良健康后果（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，因为它鼓励使用不断增加的剂量来恢复药物的初始效果。然而，很少有研究调查耐受性如何增加酒精滥用的风险。拟议的研究通过药物改变控制和调节行为的基本机制的能力的变化来衡量耐受性对滥用潜力的贡献。这项研究的发现将有助于理解饮酒者对酒精的急性行为损害影响的易感性如何通过促进持续的酗酒模式而成为后来酒精依赖的早期发病风险因素。该研究策略还将为测试神经认知机制在现有药物治疗中的作用提供方法，如纳曲酮和阿坎普罗酸，以及一些可能通过神经认知控制机制起作用的研究药物。

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.