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，延长的杏仁核在压力-奖赏相互作用中发挥关键作用，这种相互作用可能介导对慢性酒精暴露的关键行为反应。我们证明，慢性间歇性酒精暴露上调CRF受体依赖的谷氨酸释放，以及延伸杏仁核谷氨酸突触的突触后NMDA受体功能。我们建议测试一个“两次击中”的模型，在这个模型中，慢性酒精暴露和戒断产生的情感干扰依赖于扩展的杏仁核谷氨酸突触在突触前和突触后的协调调节。我们提出了一系列实验来描绘CRF受体信号调节谷氨酸突触的机制，并探索酒精暴露和戒断后NMDA受体功能的变化。我们进一步建议探索这些过程的中断对酒精戒断诱导的抑郁行为的影响。

 DESCRIPTION (provided by applicant): Alcoholism is a tremendous health and financial burden on our society. A growing literature indicates that the extended amygdala plays a key role in stress-reward interactions that may mediate key behavioral responses to chronic alcohol exposure. We demonstrated that chronic intermittent alcohol exposure up regulates CRF receptor dependent augmentation of glutamate release, as well as postsynaptic NMDA receptor function at extended amygdala glutamate synapses. We propose here to test a "two-hit" model, whereby affective disruptions produced by chronic alcohol exposure and withdrawal depend upon the coordinated pre- and postsynaptic regulation of extended amygdala glutamate synapses. We propose a series of experiments to map out mechanisms by which CRF receptor signaling regulates glutamate synapses, and to explore the alterations in NMDA receptor function that occur with alcohol exposure and withdrawal. We further propose to explore the impact of disruption of these processes on alcohol-abstinence induced depressive behaviors.