8/8 NADIA UO1 Adolescent Alcohol and Decision Making

8/8 NADIA UO1 青少年酒精与决策

• 批准号: 9762555
• 负责人: Paul E. M. Phillips
• 金额: $ 17.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762555
• 关键词: Adolescence; Adolescent; Adult; Age; Agonist; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Attitude; Behavior; Behavioral; Brain; Characteristics; Chemosensitization; Choice Behavior; Corpus striatum structure; Coupled; Data; Decision Making; Development; Disinhibition; Dopamine; Dose; Drug abuse; Drug usage; Ethanol; Exposure to; Future; Glutamates; Goals; Human; Impairment; Incidence; Individual; Life; Link; Longevity; Measures; Mediating; Midbrain structure; Modeling; Monitor; Neurobiology; Neurons; Pathway interactions; Periodicity; Pharmacology; Phase; Preparation; Process; Protocols documentation; Public Health; Rattus; Reporting; Risk; Risk-Taking; Scanning; Signal Transduction; Societies; Therapeutic; Time; Ventral Striatum; Ventral Tegmental Area; Wit; Work; addiction; adolescent alcohol exposure; alcohol exposure; alcohol use disorder; base; binge drinking; cholinergic; clinically relevant; critical period; dopamine system; dopaminergic neuron; experience; experimental study; in vivo; mature animal; mesolimbic system; neurochemistry; neurotransmission; pedunculopontine tegmentum; preference; public health relevance; receptor; response; reward processing; risk mitigation; transmission process; underage drinking

 DESCRIPTION (provided by applicant): Adolescent alcohol use remains a major public health concern due in part to evidence implicating the age of initial alcohol use as a strong predictor fo the development of alcohol use disorders in adulthood. Recent reports evaluating the impact of drug abuse on society conclude that alcohol ranks as the most harmful of all abused substances. In addition, despite continuing efforts to curb its use, alcohol remains the most commonly used and abused substance among adolescents. That such experience can be antecedent to problem drinking has been recognized for some time; that such experience may also have long-lasting effects on decision- making processes is a relatively recent consideration. Moreover, it has been suggested that such deficits in decision making may represent a vulnerability to addiction. Indeed, people who engage in binge drinking at an early age show later deficits in decision making and increased likelihood of developing alcohol abuse problems. However, interpretation of these reports in humans has remained challenging due to the difficulty in separating the specific consequences of early drug use on future behavior from pre-existing factors that may contribute throughout the lifespan. We have demonstrated that rats exposed to alcohol during adolescence make maladaptive, risky choices as adults. This impairment represents a unique vulnerability of the developing brain as we have also shown that adult rats given identical exposure do not show this deficit. Adolescence has been characterized as a time of heightened risk-taking behavior in humans. Moreover, adolescence is a critical period of maturation when brain development, including that of the mesolimbic dopamine (DA) system, may be disrupted by alcohol. Mesolimbic DA is implicated in multiple aspects of reward processing and risk preference is sensitive to manipulations of striatal phasic DA signaling. Indeed, we have shown that striatal phasic DA release in response to risky options relative to safe options is significantly increased in alcohol-exposed rats. Further, there is a relative disinhibition in DA signaling during adolescence itself. Therefore, an appealing theoretical approach has been to link maturational changes in DA systems with behavioral changes in decision making and to posit that early life alcohol use confers a neurobiological profile that promotes persistent maladaptive decision making into adulthood. However, our findings to date are based on low levels of exposure that model recreational alcohol use while one of the defining features of use in human adolescents is a high incidence of binge drinking. Thus, in this proposal we aim to expand the scope and clinical relevance of our work by examining the consequences of binge alcohol use, which predominates in adolescence and is achieved by the NADIA AIE protocol. We hypothesize that increased risk bias, characteristic of the adolescent period, is attributable to mesolimbic DA systems and that exposure to AIE alters these circuits, resulting in a circuit-specific potentiation of midbrain DA neuron activity and persistent maladaptive decision making in adulthood.

 描述（由申请人提供）：青少年饮酒仍然是一个主要的公共卫生问题，部分原因是有证据表明首次饮酒的年龄是成年期酒精使用障碍发展的有力预测因素。最近评估药物滥用对社会影响的报告得出的结论是，酒精是所有滥用物质中危害最大的。此外，尽管不断努力遏制酒精的使用，但酒精仍然是青少年中最常用和滥用的物质。一段时间以来，人们已经认识到这种经历可能是酗酒问题的先兆。这种经验也可能对决策过程产生长期影响，这是一个相对较新的考虑。此外，有人认为，这种决策缺陷可能代表着容易上瘾。事实上，年轻时酗酒的人会在以后的决策中表现出缺陷，并增加出现酗酒问题的可能性。然而，对人类这些报告的解释仍然具有挑战性，因为很难将早期吸毒对未来行为的具体后果与可能在整个生命周期中起作用的预先存在的因素区分开来。我们已经证明，在青春期接触酒精的老鼠成年后会做出适应不良、危险的选择。这种损伤代表了发育中大脑的独特脆弱性，因为我们还表明，接受相同暴露的成年大鼠不会表现出这种缺陷。青春期被认为是人类冒险行为加剧的时期。此外，青春期是大脑发育的关键时期，包括中脑边缘多巴胺（DA）系统的发育，可能会受到酒精的干扰。中脑边缘 DA 涉及奖励处理的多个方面，风险偏好对纹状体相位 DA 信号的操纵敏感。事实上，我们已经表明，在暴露于酒精的大鼠中，相对于安全选择，纹状体对危险选择的阶段性 DA 释放显着增加。此外，还有 是青春期期间 DA 信号传导的相对去抑制。因此，一种有吸引力的理论方法是将 DA 系统的成熟变化与决策中的行为变化联系起来，并假设生命早期饮酒会产生一种神经生物学特征，从而促进成年后持续做出不适应的决策。然而，我们迄今为止的研究结果是基于低水平的暴露，模拟了娱乐性酒精的使用，而人类青少年使用酒精的定义特征之一是酗酒的高发生率。因此，在本提案中，我们的目标是通过检查酗酒的后果来扩大我们工作的范围和临床相关性，酗酒在青春期占主导地位，并通过 NADIA AIE 协议实现。我们假设，青少年时期特有的风险偏倚增加可归因于中脑边缘 DA 系统，而暴露于 AIE 会改变这些回路，导致中脑 DA 神经元活动的回路特异性增强以及成年期持续的适应不良决策。