7/8 NADIA UO1 Adolescent Alcohol and Neurocircuitry Mediating Ethanol Reinforcement

7/8 NADIA UO1 青少年酒精和神经回路介导的乙醇强化

• 批准号: 9762557
• 负责人: ZACHARY Aaron RODD
• 金额: $ 31.59万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762557
• 关键词: Adolescence; Adolescent; Adult; Alcohol consumption; Alcoholism; Alcohols; American; Amygdaloid structure; Animal Model; Anti-Anxiety Agents; Anxiety; Brain; Breeding; Cell Nucleus; Child; Choline O-Acetyltransferase; Chronic; Collaborations; Complex; Consumption; DNA Methylation; Data; Decision Making; Dendritic Spines; Dopamine; Drug Addiction; Epigenetic Process; Ethanol; Family history of; Genes; Genetic Predisposition to Disease; Goals; Grant; HDAC2 gene; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Impulsivity; Mediating; Microinjections; Morphology; Motivation; Neuroimmune; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Pharmacology; Property; Psychological reinforcement; Rattus; Reporting; Research; Rewards; Self Administration; Site; Structure; Sucrose; System; Testing; Time; TimeLine; Ventral Tegmental Area; Wistar Rats; Withdrawal; adolescent alcohol exposure; adolescent alcohol risk; alcohol measurement; alcohol preferring rats; alcohol reinforcement; design; discount; discounting; drug reward; gamma-Aminobutyric Acid; high school; inhibitor/antagonist; neuroadaptation; neurochemistry; periadolescent; preference; promoter; public health relevance; reinforcer; response; underage drinking

 DESCRIPTION (provided by applicant): The vast majority of American children begin consuming alcohol prior to high school graduation and episodes of heavy ethanol consumption increase over time (Johnson et al., 1999, 2009). A family history of alcoholism increases the risk that adolescent alcohol consumption is associated with adult alcoholism (Agrawal et al., 2009). Periadolescent ethanol consumption by alcohol-preferring (P) rats increases the reinforcing properties of EtOH in the posterior ventral tegmental area (pVTA) during adulthood (Toalston et al., 2014). NADIA- generated research has indicated that adolescent intermittent ethanol (AIE) exposure results in persistent alterations in neuroimmune factors, choline acetyltransferase (ChAT), increased anxiety, and changes in histone acetylation altering neurocircuitry (Vetreno et al., 2014; Sakharkar et al., 2014). As a new component of the NADIA Consortium, the long-range objectives of this study are to determine the effects of AIE on the motivational, reinforcing and anxiolytic properties of EtOH during adulthood within the pVTA and central nucleus of the amygdala (CeA). The impact of a genetic predisposition to high alcohol consumption on the effects of AIE will be determined by making assessments in P rats. The overall hypothesis is that AIE results in lasting neurotransmitter system, epigenetic, and structural alterations in regions critical for motivation, reinforcement, and anxiety. The goals of the application are 1) to assess alterations in the reinforcing properties of EtOH in the pVTA and CeA produced by AIE, 2) to evaluate the neurochemical response to EtOH in the pVTA induced by AIE, 3) to determine if histone deacetylase (HDAC) inhibitor treatment reverses the alterations produced by AIE, 4) to determine the impact of AIE on probabilistic decision-making. In Aim 1, we will test the hypothesis that AIE induced neuroadaptations within the pVTA alter EtOH reinforcement and the neurochemical response to EtOH during adulthood. In Aim 2, we will test the hypothesis that AIE induced neuroadaptations within the pVTA can be reversed by site specific administration of HDAC inhibitor during adulthood. In Aim 3, we will test the hypothesis that AIE induced neuroadaptations within the CeA alter the reinforcing and anxiolytic properties of EtOH during adulthood. In Aim 4, we will test the hypothesis that AIE has altered the probabilistic decision-making (an animal model of impulsivity) during adulthood. This is a highly significant project that will attempt to elucidate the complex factors that underlie the effects of AIE on adult EtOH usage.

 描述（由申请人提供）：绝大多数美国儿童在高中毕业前开始饮酒，并且大量乙醇消耗的事件随着时间的推移而增加（约翰逊等人，1999年、2009年）。酒精中毒的家族史增加了青少年酒精消费与成人酒精中毒相关的风险（Agrawal等人，2009年）。酒精偏好（P）大鼠的青春期前乙醇消耗增加了成年期后腹侧被盖区（pVTA）中EtOH的增强特性（Toalston等人，2014年）。NADIA产生的研究表明，青少年间歇性乙醇（AIE）暴露导致神经免疫因子、胆碱乙酰转移酶（ChAT）的持续改变、焦虑增加以及组蛋白乙酰化改变神经回路的变化（Vetreno等人，2014; Sakharkar等人，2014年）。作为NADIA联盟的一个新的组成部分，本研究的长期目标是确定AIE对动机、强化和心理活动的影响。 和抗焦虑性质的乙醇在成年期内的pVTA和中央核的杏仁核（CeA）。将通过在P大鼠中进行评估来确定高饮酒量遗传倾向对AIE效应的影响。总的假设是，AIE导致持久的神经递质系统，表观遗传和结构改变的区域的关键动机，强化和焦虑。应用程序的目标是1） 评估由AIE产生的pVTA和CeA中EtOH的增强性质的改变，2）评估由AIE诱导的pVTA中对EtOH的神经化学反应，3）确定组蛋白脱乙酰酶（HDAC）抑制剂治疗是否逆转由AIE产生的改变，4）确定AIE对概率决策的影响。在目标1中，我们将测试的假设，AIE诱导的神经适应内的pVTA改变乙醇的强化和神经化学反应，乙醇在成年期。在目的2中，我们将检验以下假设：在成年期，通过HDAC抑制剂的位点特异性给药，可以逆转pVTA内AIE诱导的神经适应。在目标3中，我们将测试的假设，AIE诱导的神经适应内的CeA改变增强和抗焦虑的性质，乙醇在成年期。在目标4中，我们将检验AIE已经改变了成年期的概率决策（冲动的动物模型）的假设。这是一个非常重要的项目， 将试图阐明AIE对成人EtOH使用影响的复杂因素。