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

 描述(申请人提供)：绝大多数美国儿童在高中毕业前就开始饮酒，大量饮酒的事件随着时间的推移而增加(Johnson等人，1999,2009)。家族酗酒史增加了青少年饮酒与成人酗酒有关的风险(Agrawal等人，2009年)。在成年期，嗜酒(P)大鼠在青春期饮用酒精会增加EtoH在后腹侧被盖区(PVTA)的增强特性(Toalston等人，2014年)。由NADIA产生的研究表明，青春期间歇性乙醇(AIE)暴露会导致神经免疫因子、胆碱乙酰转移酶(ChAT)的持续变化、焦虑增加，以及改变神经回路的组蛋白乙酰化改变(Vetreno等人，2014；Sakharkar等人，2014)。作为NADIA联盟的一个新成员，本研究的长期目标是确定AIE在激励、强化 成年后，乙醇在pVTA和杏仁中央核(CEA)内具有抗焦虑作用。对高酒精摄入的遗传倾向对AIE影响的影响将通过对P鼠的评估来确定。总体假设是，AIE导致持久的神经递质系统、表观遗传学和对动机、强化和焦虑至关重要的区域的结构变化。应用程序的目标是1)到 评估AIE产生的pVTA和CEA中乙醇增强特性的变化，2)评估AIE诱导的pVTA中乙醇的神经化学反应，3)确定组蛋白脱乙酰酶(HDAC)抑制剂治疗是否逆转AIE产生的变化，4)确定AIE对概率决策的影响。在目标1中，我们将检验AIE在成年期间诱导pVTA内的神经适应改变无水乙醇强化以及对无水乙醇的神经化学反应的假说。在目标2中，我们将测试AIE诱导的pVTA内的神经适应可以通过成年期部位特异性地给予HDAC抑制剂来逆转的假设。在目标3中，我们将检验AIE在CEA内诱导的神经适应在成年期改变EtoH的增强和抗焦虑特性的假设。在目标4中，我们将检验AIE已经改变了成年期概率决策(冲动的动物模型)的假设。这是一个非常重要的项目 我将试图阐明AIE对成人乙醇使用的影响的复杂因素。

 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.