Impact of adolescent intermittent ethanol on adult social reward and anxiety

描述（由申请人提供）：青春期是压力敏感大脑区域发生重大转变的时期，这些区域在处理奖励和社会/情感刺激中起关键作用，并在对这些区域施加调节控制的区域中发挥作用。鉴于物质的持久影响最有可能发生在对这些物质敏感的系统正在发生发育变化的时候，我们假设青少年间歇性乙醇（AIE）暴露将对社会行为和乙醇的社会奖励和厌恶效应产生持久影响，导致成人摄入量持续升高，部分原因是酒精的社会焦虑特性。事实上，酒精的社会奖励效应对于青春期开始饮酒和社交焦虑个体升级为重度饮酒至关重要，社交焦虑的酗酒者比不依赖社交焦虑的个体表现出更大程度的社交障碍。拟议的研究将调查自愿和实验者管理的青少年间歇性酒精（AIE）对后来的社交焦虑和奖励的影响，酒精对抗这些社会行为中持久扰动的功效，以及对后来自愿摄入乙醇的影响，以及这些影响背后的神经/遗传适应。利用NADIA提供的协同效应，本研究将探讨以下目的：(1)检验AIE是否会增加成年期社交环境下焦虑样行为的基线水平，并加剧应激性社交焦虑，并确定急性乙醇对扭转这种社交焦虑的效果；(2)确定AIE暴露是否会破坏社会刺激的奖励和/或享乐价值，这些改变是否会因压力而进一步加剧，以及急性乙醇对逆转这些影响的效果；(3)评估AIE是否会增强成年期的乙醇饮用，降低对乙醇厌恶特性的敏感性，以及这些影响是否会因成年期的社会环境而进一步加剧；(4)通过测量社交刺激下伏隔核实时多巴胺释放量和关键边缘区域多巴胺相关基因表达，探讨AIE对成年期多巴胺传递的影响。

DESCRIPTION (provided by applicant): Adolescence is a time of considerable transformation in stress-sensitive brain regions that play key roles in the processing of rewarding and social/emotional stimuli and in areas that exert regulatory control over these regions. Given that lasting effects of substances are most likely to occur when systems sensitive to those substances are changing developmentally, we hypothesize that adolescent intermittent ethanol (AIE) exposure will induce lasting effects on social behavior and on the social rewarding and aversive effects of ethanol, leading to persistent elevations in adult intake due in part to alcohol's social anxiolytic properties. Indeed, social rewarding effects of alcohol are critical for the initiation of alcohol use in adolescence and escalation to heavy drinking among individuals with social anxiety, with socially anxious alcoholics showing greater levels of social impairment than non-dependent, socially anxious individuals. The proposed studies will investigate the consequences of voluntary and experimenter-administered adolescent intermittent alcohol (AIE) on later social anxiety and reward, the efficacy of alcohol for countering these lasting perturbations in social behavior, and the impact on later voluntary intake of ethanol, along with neural/genetic adaptations underlying these effects. Using synergisms provided by the NADIA, the proposed research will address the following aims: (1) test whether AIE increases baseline levels of anxiety-like behavior under social circumstances in adulthood and exacerbates stress-induced social anxiety, and determine the efficacy of acute ethanol for reversing this social anxiety; (2) determine whether AIE exposure disrupts the rewarding and/or hedonic value of social stimuli, whether these alterations are further exacerbated by stress, and the efficacy of acute ethanol for reversing these effects; (3) assess whether AIE enhances ethanol drinking in adulthood and decreases sensitivity to the aversive properties of ethanol, and whether these effects of AIE are further exacerbated by social context in adulthood; (4) investigate AIE effects on dopamine transmission during adulthood by measuring real-time dopamine release in nucleus accumbens in response to social stimuli and assessing dopamine-related gene expression in key limbic regions. PUBLIC HEALTH RELEVANCE: The proposed investigations of lasting effects of adolescent alcohol exposure on social anxiety, alcohol's anxiolytic properties, and underiying neural/genetic adaptations are of considerable relevance, given the importance of alcohol's social rewarding properties in initiating use and escalating to heavy drinking among individuals with social anxiety, along with the greater social impairment seen in socially anxious alcoholics.