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

项目摘要/摘要 主要研究部分4 酒精是美国青少年最广泛使用的物质之一，酗酒和酗酒 在目前近三分之二的未成年人饮酒者中，这一点很明显。这些酗酒和酗酒的高比率是 令人担忧的是，因为即使是偶尔酗酒的青少年也更有可能表现出饮酒 在以后的生活中，精神障碍和其他不良后果。年轻人主要在社交场合喝酒， 尽管这种背景特殊性--更不用说对社会后果的敏感度的性别差异--一直是 很少有人调查过。使用青春期的老鼠模型，我们已经显示出显著的质的性别差异 酒精导致青少年大量社交饮酒的前兆和影响。高社会性 男性饮酒与高社会活动和对社交便利的敏感度增强有关。 酒精的影响，而在青春期女性中，社交饮酒水平越高，就越高 社交焦虑和对酒精的社交焦虑作用的敏感度增强。目前的建议是 旨在单独确定负责高度社会活动和对 酒精在青春期男性中诱导的社交促进作用，与与高社交焦虑和 增强女性对酒精的社交焦虑效应的敏感度。目标大脑区域是 社交饮酒表型高的男性和女性的差异激活将通过以下方法确定 转基因CFos-LacZ大鼠及c-Fos的X-Gal染色。然后，将使用Daun02程序选择性地 灭活特定靶区中由社会刺激单独激活或在 与急性酒精中毒的结合，以及这种失活对随后的社交饮酒的后果确定 在男性和女性高社交饮酒者中。我们预计，社交网络激活的神经系综失活 社交活跃度高的男性单独或与急性酒精中毒相结合将减少社交饮酒 在这些动物中，而在社交焦虑程度较高的青少年中，神经元群激活了失活 女性通过社会刺激将减少这些女性的社交饮酒。鉴于大脑的关键重要性 加压素/催产素多肽系统在调节社交行为和社交焦虑方面，我们还将测试 假设男性大量社交饮酒与脑血管加压素V1a的过度活动有关 受体，而大脑催产素系统功能低下导致大量社交饮酒 青春期女性。这些假说将通过对蛋白质的评估进行神经药理学检验。 与性别相关的脑区催产素和加压素及其受体水平 高饮酒表型。这项提案中概述的工作将是第一批检查神经的工作之一。 前驱物质中显著的质量性别差异的贡献者导致高社交饮酒 青少年，对于制定新的、针对性别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.