Alcohol action on extended amygdala glutamate synapses

描述(申请人提供)：酗酒是我们社会的一个巨大的健康和经济负担。越来越多的文献表明，一系列相互关联的大脑区域被称为延伸的杏仁核，在酒精相关行为中发挥着关键作用。在孤立的研究中，我们和其他人已经确定了这些区域突触对急性和慢性酒精暴露的适应。在这里，我们建议进行实验，平行检查这一回路中的关键点，以了解它们对常见酒精治疗方案的反应，以更好地确定乙醇和乙醇停药的协同效应。此外，我们将通过使用一种新的NMDA受体亚单位NR2B条件性基因敲除小鼠结合病毒导向的基因敲除策略来评估这些作用所涉及的分子机制。总之，拟议的工作将开始定义可能在与慢性酒精摄入相关的病理适应和行为中发挥关键作用的特定机制，从而为治疗开发提供新的潜在机会。 与公共健康相关：酗酒给我们的社会带来了巨大的健康和经济负担。目前，我们对酒精中毒所涉及的大脑回路的了解还远远不完整。这些拟议研究的成功完成将带来关于可能参与酒精中毒的神经元的重要新信息，可能为治疗开发创造新的靶点。

DESCRIPTION (provided by applicant): Alcoholism is a tremendous health and financial burden on our society. A growing literature indicates that a series of interconnected brain regions referred to as the extended amygdala plays a key role in alcohol-related behaviors. In isolated studies, we and others have identified adaptations that occur at synapses in these regions in response to acute and chronic ethanol exposure. Here, we propose experiments to in parallel examine key points in this circuitry for their responses to a common alcohol treatment regimen, to better determine the concerted effects of ethanol and ethanol withdrawal. Moreover, we will assess molecular mechanisms involved in these actions through the use of a new conditional knockout mouse for the NMDA receptor subunit NR2B combined with a viral-directed knockout strategy. In total, the proposed work will begin to define specific mechanisms likely to play key roles in pathological adaptations and behaviors associated with chronic alcohol intake, thus providing new potential opportunities for therapeutic development. PUBLIC HEALTH RELEVANCE: Alcoholism poses an enormous health and financial burden on our society. Currently, our understanding of the brain circuitries involved in alcoholism is far from complete. The successful completion of these proposed studies will result in important new information about neurons that may be involved in alcoholism, potentially creating new targets for therapeutics development.