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（由申请人提供）：我们目前在NIAAA关于成年期青少年饮酒神经生物学（NADIA）的联盟中的工作已经产生了关于青少年间歇性乙醇（AIE）后果的四个至关重要的关键发现。这些后果：a）在青春期早期-中期与晚期暴露之间存在显著差异; B）具有性别特异性;包括c）社交焦虑的诱导，以及d）酒精典型表型的持续性，包括酒精对成年期的酒精典型反应。我们目前的建议将解决这项工作中出现的关键差距。目标1将评估早期-中期青少年AIE暴露是否（类似于青春期早期开始使用）改变了受皮质下边缘系统影响的社会/情感/奖励领域，该系统的活动在当时特别普遍，而青春期晚期的AIE（类似于人类的青少年后期/成年期，其中酗酒特别明显）在要求成熟较晚的前额区完整性的任务中产生改变。预计影响是性别特异性的，早期AIE影响在男性中更明显，晚期AIE后果在女性中更明显。目标2将集中在神经基板的显着社会焦虑样行为诱导的早期AIE在男性，重点是两个肽的关键 参与社会行为的激素：催产素（OXT）和加压素（AVP）。将使用精神药理学方法沿着评估OXT、AVP及其受体的水平，以及参与社交焦虑的两个关键区域（杏仁核和下丘脑）中的相关表观遗传修饰，以检验男性社交焦虑与OXT和AVP平衡向AVP的转变相关的假设。最后，目标3将评估是否持续到成年期的良好表征的典型酒精敏感性， AIE涉及兴奋-抑制平衡的扰动。精神药理学和分子方法将被用来测试这一假设，特别强调谷氨酸NR 2B和AMPA和突触外GABAA受体沿着囊泡转运蛋白的比例。目的2和3的研究将着眼于确定逆转AIE效应的药物治疗方法。