Impact of adolescent intermittent ethanol on adult social reward and anxiety

描述(申请人提供)：青春期是压力敏感型大脑区域的相当大的转变时期，这些区域在奖励和社会/情绪刺激的处理过程中发挥关键作用，并且在对这些区域施加调节控制的区域中发挥关键作用。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)暴露将对社会行为以及乙醇的社会奖赏和厌恶效应产生持久影响，导致成人摄入量持续增加，部分原因是酒精的社交焦虑特性。的确，酒精的社会回报效应对于青少年开始饮酒以及在有社交焦虑的个人中升级为酗酒至关重要，社交焦虑的酗酒者表现出比不依赖的、社交焦虑的个人更严重的社会损害。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后果，酒精对抵消这些社会行为中的这些持久干扰的有效性，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，这项拟议的研究将解决以下目标：(1)测试AIE是否会增加成年后社交环境中焦虑样行为的基线水平，并加剧应激诱导的社交焦虑，并确定急性乙醇对逆转这种社交焦虑的有效性；(2)确定AIE暴露是否扰乱了社会刺激的奖赏和/或享乐价值，这些变化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有效性；(3)评估AIE是否增加了成年后的酒精饮用量，降低了对酒精厌恶特性的敏感性，以及AIE的这些影响是否会因成年后的社会背景而进一步加剧；(4)通过测量伏隔核多巴胺对社会刺激的实时释放，并评估关键边缘区域的多巴胺相关基因表达，研究AIE对成年期间多巴胺传递的影响。 公共卫生相关性：鉴于酒精的社会回报特性在社交焦虑症患者开始使用酒精并升级为大量饮酒方面的重要性，以及社交焦虑症患者的更大社会损害，拟议的青少年酒精暴露对社交焦虑、酒精的抗焦虑特性以及潜在的神经/遗传适应的持久影响的调查具有相当大的相关性。

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.