2/8 NADIA UO1 Adolescent alcohol: exposure timing, sex differences and neural contributors to persistent anxiety and adolescent phenotypes

 描述(由申请人提供)：我们目前在NIAAA协会关于青少年成年饮酒的神经生物学(NAIDA)的工作中，就青少年间歇性乙醇(AIE)的后果产生了四个至关重要的关键发现。这些后果：a)在青春期早期、中期和晚期的暴露有很大的不同；b)有性别差异；以及c)诱发社交焦虑，以及d)青少年典型的表型持续存在，包括青春期对酒精的典型反应进入成年期。我们目前的提案将解决这项工作中出现的严重差距。目的1将评估青春期早期和中期的AIE暴露(类似于青春期早期开始使用)是否改变了受皮质下边缘系统影响的社交/情感/奖赏领域，而AIE在青春期后期(类似于人类青春期后期/成年期初起，酗酒特别明显)会导致要求晚成熟前额叶区域完整的任务的改变。据预测，影响是性别特有的，早期的AIE影响在男性中更为明显，而晚期的AIE后果在女性中更为明显。目标2将集中在男性早期AIE诱导的显著社交焦虑样行为的神经基础上，重点关注两个关键的多肽 参与社会行为：催产素(OXT)和加压素(AVP)。精神药理学方法以及对OXT、AVP及其受体水平的评估，以及涉及社交焦虑的两个关键区域(杏仁核和下丘脑)的相关表观遗传修饰，将被用来检验这一假设，即男性的社交焦虑与OXT和AVP向AVP的平衡转变有关。最后，目标3将评估具有良好特征的青少年典型的酒精敏感性是否会持续到成年后 AIE与兴奋性-抑制性平衡的扰动有关。将使用精神药理学和分子方法来验证这一假说，特别强调谷氨酸NR2B和AMPA和突触外GABAA受体以及囊泡转运体比率。AIMS 2和AIMS 3的研究将着眼于确定逆转AIE效应的药物治疗方法。

 DESCRIPTION (provided by applicant): Our current work in the NIAAA consortium on the Neurobiology of Adolescent Drinking in Adulthood (NADIA) has yielded four key findings of critical importance regarding the consequences of adolescent intermittent ethanol (AIE). These consequences: a) differ dramatically with exposures during early-mid versus late adolescence; b) are sex-specific; and include c) induction of social anxiety, and d) the persistence of adolescent-typical phenotypes, including adolescent-typical responses to ethanol into adulthood. Our current proposal will address critical gaps arising from this work. Aim 1 will assess whether early-mid adolescent AIE exposure (analogous to early initiation of use in adolescence) alters social/affective/reward domains influenced by subcortical limbic systems whose activity is particularly prevalent at that time, whereas AIE in late adolescence (analogous to the late adolescent/emerging adulthood period in humans where binge drinking is particularly pronounced) produces alterations in tasks requiring integrity of late maturing prefrontal areas. Effects are predicted to be sex-specific, with early AIE effects more pronounced in males and late AIE consequences in females. Aim 2 will focus on neural substrates underlying the marked social anxiety-like behavior induced by early AIE in males, with a focus on two peptides critically involved in social behavior: oxytocin (OXT) and vasopressin (AVP). Psychopharmacological approaches along with assessment of levels of OXT, AVP and their receptors, as well as associated epigenetic modifications in two key regions involved in social anxiety (amygdala and hypothalamus), will be used to test the hypothesis that social anxiety in males is associated with a shift in balance of OXT and AVP toward AVP. Lastly, Aim 3 will assess whether the persistence of well-characterized adolescent-typical ethanol sensitivities into adulthood following AIE relates to perturbations in excitatory-inhibitory balance. Both psychopharmacological and molecular approaches will be used to test this hypothesis, with a particular emphasis on glutamate NR2B and AMPA and extrasynaptic GABAA receptors along with vesicular transporter ratios. Studies in both Aims 2 and 3 will be conducted with an eye toward identification of pharmacotherapeutic approaches to reverse AIE effects.