8/8 NADIA UO1 Adolescent Alcohol and Decision Making

8/8 NADIA UO1 青少年酒精与决策

• 批准号: 9025530
• 负责人: Jeremy J. Clark
• 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/9025530
• 关键词: Adolescence; Adolescent; Adult; Age; Agonist; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Attitude; Behavior; Behavioral; Brain; Characteristics; Chemosensitization; Choice Behavior; Control Animal; 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; Preparation; Process; Protocols documentation; Public Health; Rattus; Relative (related person); Reporting; Risk; Risk-Taking; Scanning; Signal Transduction; Societies; Staging; Therapeutic; Time; Ventral Striatum; Ventral Tegmental Area; Wit; Work; addiction; adolescent alcohol; alcohol exposure; alcohol use disorder; base; binge drinking; cholinergic; clinically relevant; critical period; dopamine system; dopaminergic neuron; experience; in vivo; mature animal; mesolimbic system; neurochemistry; neurotransmission; pedunculopontine tegmentum; preference; public health relevance; receptor; research study; 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一个强有力的预测因素。最近评价药物滥用对社会影响的报告得出结论，酒精是所有滥用物质中危害最大的。此外，尽管不断努力限制酒精的使用，但酒精仍然是青少年中最常用和滥用的物质。这种经历可能是酗酒问题的先兆，这一点已经被认识到了一段时间;这种经历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，这种决策缺陷可能意味着容易成瘾。事实上，那些在幼年时就酗酒的人在决策方面表现出了后来的缺陷，并增加了发展酒精滥用问题的可能性。然而，这些报告在人类中的解释仍然具有挑战性，因为很难将早期药物使用对未来行为的特定后果与可能在整个生命周期中起作用的预先存在的因素分开。我们已经证明，在青春期接触酒精的老鼠在成年后会做出适应不良的、危险的选择。这种损伤代表了发育中的大脑的独特脆弱性，因为我们还表明，给予相同暴露的成年大鼠不会显示出这种缺陷。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，可能会被酒精破坏。中脑边缘DA参与奖励处理的多个方面，并且风险偏好对纹状体阶段性DA信号的操纵敏感。事实上，我们已经表明，纹状体阶段性DA释放响应于风险的选择相对于安全的选择显着增加在酒精暴露的大鼠。此外，在 是青春期DA信号的相对去抑制。因此，一个有吸引力的理论方法已被链接到成熟的DA系统的变化与决策的行为变化，并重申，早期生活中的酒精使用赋予神经生物学的配置文件，促进持续适应不良的决策到成年。然而，迄今为止，我们的研究结果是基于低水平的暴露模型娱乐性酒精使用，而人类青少年使用的定义特征之一是酗酒的发生率很高。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，酗酒主要发生在青春期，并通过NADIA AIE协议实现。我们假设，增加风险偏见，青少年时期的特点，是由于中脑边缘DA系统和暴露于AIE改变这些电路，导致在电路特定的增强中脑DA神经元的活动和持续适应不良的决策在成年期。