4/8: INIA Stress and Chronic Alcohol Interactions: Impact of stress mediated locus coeruleus dysregulation on cognitive control and excessive drinking

项目摘要/摘要 酒精使用障碍与慢性压力和焦虑之间存在强烈的共病。内在功能障碍 酒精和压力的重叠神经靶点可能促进这种共存表型的发展。 蓝斑去甲肾上腺素(LC-NE)系统对酒精和应激都敏感，并发挥着重要的作用。 在认知和情绪调节行为中起着重要作用。慢性后LC-NE环路的可塑性 压力和酒精可以产生前馈效应，通过HPA轴和 通过扰乱前额叶皮质(PFC)功能来降低认知控制能力。这种压力的后果是- 认知“双重打击”是指饮酒需求的增加和饮酒控制力的降低。我们的预赛 有证据表明，慢性间歇性酒精暴露除了反复游泳压力外，还会破坏 与酒精或压力相比，PFC依赖认知和过度饮酒的增加更多。在这些 研究我们将研究LC作为应激/酒精适应不良的关键靶点以及LC-NE的可能性 靶向治疗可缓解应激/酒精引起的执行功能障碍、焦虑升高和 过度饮酒。该项目将为慢性应激后LC-NE功能障碍的作用提供新的见解 还有酒。我们的研究结果将确定过量饮酒背后的新电路变化和 去甲肾上腺素靶向治疗酒精使用障碍患者认知和情绪障碍的可能性。

PROJECT SUMMARY/ABSTRACT There is strong comorbidity between alcohol use disorders and chronic stress and anxiety. Dysfunction within overlapping neural targets of alcohol and stress may facilitate the development of this comorbid phenotype. The locus coeruleus norepinephrine (LC-NE) system is sensitive to both alcohol and stress and plays an important role in cognitive and emotional regulation of behavior. Plasticity within LC-NE circuits after chronic stress and alcohol can produce feed-forward effects, elevating stress and anxiety via the HPA axis and decreasing cognitive control by disrupting prefrontal cortex (PFC) function. The consequence of this stress- cognition “double-hit” is an increased need to drink and a decreased control over drinking. Our preliminary evidence demonstrates that chronic intermittent ethanol exposure in addition to repeated swim stress, disrupts PFC dependent cognition and increases excessive drinking more than either ethanol or stress alone. In these studies we will investigate the LC as a key target of stress/ethanol maladaptations and the potential for LC-NE targeted therapeutics to ameliorate stress/ethanol induced executive dysfunction, elevated anxiety, and excessive drinking. This project will provide new insights into the role of LC-NE dysfunction after chronic stress and alcohol. Our results will identify novel circuit changes underlying excessive alcohol consumption and the potential for NE targeted therapies in treating cognitive and emotional dysfunction in alcohol use disorders.