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

2/8 NADIA UO1 青少年酒精：暴露时间、性别差异以及持续焦虑和青少年表型的神经因素

• 批准号: 9026889
• 负责人: LINDA PATIA SPEAR
• 金额: $ 34.83万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-05 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026889
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Affective; Age; Agonist; Alcohol abuse; Alcohol consumption; Alcoholism; Amygdaloid structure; Anxiety; Area; Behavioral; Brain region; Choline O-Acetyltransferase; Collaborations; Data; Dendritic Spines; Dependency; Dose; Epigenetic Process; Equilibrium; Ethanol; Extinction (Psychology); Eye; Female; GABA transporter; Gene Expression; Glutamates; Goals; Hippocampus (Brain); Human; Hypothalamic structure; Immunohistochemistry; Limbic System; Membrane; Modification; Molecular; Morphology; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Nucleus Accumbens; OXT gene; Oxytocin; Pattern; Peptides; Phenotype; Prefrontal Cortex; Production; Proteins; Rewards; Role; Sex Characteristics; Social Behavior; Social Facilitation; Specificity; Surface; Synapses; System; Testing; Time; Vasopressins; Vertebral column; Work; adolescent alcohol; adolescent alcohol exposure; alcohol effect; alcohol exposure; alcohol related problem; alcohol response; alcohol sensitivity; anxiety-like behavior; basal forebrain; binge drinking; density; developmental disease; differential expression; drinking; early adolescence; emerging adulthood; excitotoxicity; ifenprodil; male; neurogenesis; psychopharmacologic; public health relevance; receptor; receptor expression; relating to nervous system; response; sex; social; social anxiety; underage drinking

 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.

 描述（由适用提供）：我们目前在NIAAA联盟的成年饮酒神经生物学（NADIA）的工作已经提出了四个关键的发现，对青少年间歇性乙醇（AIE）的后果至关重要。这些后果：a）在早期与青少年晚期期间与暴露的情况不同； b）特定于性别；包括c）诱导社交焦虑，d）青少年典型表型的持久性，包括对乙醇的青少年典型反应到成年。我们目前的建议将解决这项工作引起的关键差距。 AIM 1将评估早期中期的青春期AIE暴露（类似于早期开始使用青少年的使用）是否会改变受皮层下边缘系统影响的社会/情感/奖励领域，其活动在当时尤其普遍，而AIE则在青少年晚期（类似于最新）的青少年/杂物饮用时期的饮酒，尤其是在较晚的饮酒中，尤其是饮酒的代理，尤其是饮酒的代理，尤其是饮酒的代理。成熟的前额叶区域。效果预计是特定性别的，在男性中，早期的AIE效应在女性中的后果更为明显。 AIM 2将重点放在男性早期AIE引起的明显社交焦虑行为的基础上，重点是两个宠物 参与社会行为：氧气（OXT）和加压素（AVP）。心理药理学方法以及评估OXT，AVP及其受体的水平，以及社交动画涉及的两个关键区域（Amygdala和下丘脑）的相关表观遗传学修改，将用于测试男性社交动画与男性的社交动画与OXT和AVP平衡的转变有关。最后，AIM 3将评估特征典型的青少年乙醇敏感性是否持续到成年期 在兴奋性抑制平衡中与扰动的关系。心理药理学和分子方法都将用于检验该假设，并特别强调谷氨酸NR2B和AMPA和AMPA以及囊外GABAA受体以及囊泡转运蛋白的比率。目标2和3中的研究将旨在鉴定药物治疗方法以逆转AIE效应。