Main Research Component 4: Sex-specific neural contributors to high social drinking in adolescence

项目总结/摘要 主要研究构成部分4 酒精是美国青少年使用最广泛的物质之一，酗酒和酗酒 在近三分之二的未成年饮酒者中很明显。这些高比率的狂欢和大量饮酒是 令人担忧的是，即使是偶尔大量饮酒的青少年也更有可能表现出酒精使用， 疾病和其他不良后果在以后的生活。年轻人主要在社交场合喝酒， 尽管这种背景特异性--更不用说对社会后果敏感性的性别差异--一直是 很少调查。使用青春期的大鼠模型，我们已经显示出明显的质的性别差异， 乙醇的前体和影响导致青少年的高社交饮酒。高社会 男性饮酒与高社会活动和对社会促进的敏感性增强有关。 酒精的影响，而在青春期女性，更高水平的社会饮酒与升高的 社交焦虑和对乙醇的社交焦虑作用的敏感性增强。现时的建议是 旨在分别确定负责高社会活动和敏感性的大脑区域， 与高社交焦虑相关的区域相比， 女性对乙醇的社会抗焦虑作用的敏感性增强。目标大脑区域是 在具有高社交饮酒表型的男性和女性中的差异激活将使用 转基因cFos-LacZ大鼠和c-Fos的X-Gal染色。Daun 02程序将用于选择性地 在特定的目标区域中，由单独的社会刺激激活或 结合急性乙醇，以及这种失活对随后的社会饮酒的后果确定 男性和女性高社交饮酒者。我们认为，由社交活动激活的神经系统的失活 在社交活跃的男性中，单独或与急性EtOH结合的相互作用将减少社交饮酒 在这些动物中，而在高度社交焦虑的青少年中， 社会刺激会减少这些女性的社交饮酒。考虑到大脑的重要性 加压素/催产素肽系统在调节社会行为和社会焦虑中的作用，我们还将测试 男性社交饮酒量高与脑血管加压素V1 a过度活跃有关的假说 受体，而大脑催产素系统的功能性低活动导致高社交饮酒， 青春期的女性这些假设将通过神经生物学和蛋白质评估来检验。 催产素和加压素及其受体在大脑区域的水平与性别特异性相关， 高饮酒表型。这项提案中概述的工作将是第一批检查神经系统的工作之一。 导致高社会饮酒的前体中明显的定性性别差异的贡献者 对制定针对不同性别的新的早期预防和干预战略至关重要， 青春期酗酒。

PROJECT SUMMARY/ABSTRACT MAIN RESEARCH COMPONENT 4 Alcohol is one of the most widely used substances by American adolescents, with binge and heavy drinking evident in almost two thirds of underage current drinkers. These high rates of binge and heavy drinking are alarming, since adolescents who engage in even episodic heavy drinking are more likely to exhibit alcohol use disorders and other adverse consequences later in life. Young people predominantly drink in social situations, although this context specificity – let alone sex differences in sensitivity to social consequences – has been little investigated. Using a rat model of adolescence, we have shown pronounced qualitative sex differences in the precursors and effects of ethanol contributing to high social drinking among adolescents. High social drinking among males is associated with high social activity and enhanced sensitivity to the socially facilitating effects of ethanol, whereas in adolescent females, higher levels of social drinking are associated with elevated social anxiety and enhanced sensitivity to the socially anxiolytic effects of ethanol. The present proposal is designed to separately determine brain regions that are responsible for high social activity and sensitivity to ethanol-induced social facilitation in adolescent males, in contrast to regions related to high social anxiety and enhanced sensitivity to the socially anxiolytic effects of ethanol in females. Target brain regions that are differentially activated in males and females with high social drinking phenotypes will be determined using transgenic cFos-LacZ rats and X-Gal staining for c-Fos. The Daun02 procedure will then be used to selectively inactivate neuronal ensembles in specified target regions that were activated by the social stimulus alone or in combination with acute EtOH, and consequences of this inactivation on subsequent social drinking determined in male and female high social drinkers. We expect that inactivation of neural ensembles activated by social interactions alone or in combination with acute EtOH in high socially active males will attenuate social drinking in these animals, whereas inactivation of neuronal ensembles activated in high socially anxious adolescent females by social stimuli will diminish social drinking in these females. Given the critical importance of brain vasopressin/oxytocin peptide systems in regulation of social behavior and social anxiety, we will also test the hypothesis that high social drinking in males is associated with hyperactivity of the brain vasopressin V1a receptor, whereas functional hypoactivity of the brain oxytocin system contributes to high social drinking in adolescent females. These hypotheses will be tested neuropharmacologically and via assessment of protein levels for oxytocin and vasopressin and their receptors in the brain regions sex-specifically associated with high drinking phenotypes. The work outlined in this proposal will be among the first to examine neural contributors to the pronounced qualitative sex differences in precursors leading to high social drinking among adolescents, and are essential for creation of new, sex-specific early prevention and intervention strategies for heavy alcohol use in adolescence.