Component 7: Parsons

人类酗酒者戒断与焦虑和抑郁增加有关，而焦虑和抑郁是可以缓解的 通过持续饮酒。人们认为，这些消极的情感状态构成了主要的驱动力 用于持续饮酒。最近在实验动物身上收集的数据表明 内源性大麻素在调节焦虑相关行为方面起着重要作用。据推测， 内源性大麻素系统在引起焦虑的情况下被激活，这种激活起到了 以抑制导致焦虑样行为的神经元反应。越来越多的证据也表明 酒精暴露会改变脑内大麻素(ECB)水平，而长期酒精暴露会诱导 这一系统功能的持续变化。我们最近观察到，细胞间质水平 欧洲央行物质ANANDIMS和2-花生四烯酸甘油(2-AG)在中央显著减少 慢性酒精暴露后急性戒断时杏仁核(CEA)的变化。此外， 恢复乙醇摄入可使2-AG水平恢复到停药前的基线水平。基于 建议将ECB作为“抗应激”效应的中介人，这些发现表明ECB有缺陷 CEA中的信号可能是导致过度焦虑的敏感化焦虑样表型的基础 乙醇消耗量。本部分提出的实验将使用体内的神经化学物质。 监测和行为药理学表征ECB信号缺陷的潜在参与 在CEA中有乙醇戒断的激励作用。第一个特定目标的实验将 描述酒精依赖和戒断对基础和应激诱导的ECB功能的影响 CEA采用活体微透析。第二个特定目标的实验将利用行为测试来 描述改变的ECB功能参与CEA增加的焦虑样行为和 在酒精依赖大鼠中观察到过量的酒精消耗。拟议中的实验将评估 CEA中ECbs、GABA和谷氨酸之间的相互作用，因此这项工作与 在细胞神经生物学研究部分(Roberto/Siggins)建议的工作。所获得的结果 在这项研究中，这一组成部分可能为推动 酗酒。

Withdrawal in human alcoholics is associated with increased anxiety and depression that can be alleviated through continued drinking. It is belived that these negative affective states constitute a major driving force for continued alcohol consumption. Recent data gathered in experimental animals suggests that endogenous cannabinoids play an important role in regulating anxiety-related behaviors. It is theorized that the endocannabinoid system is activated in response to anxiogenic situations, and that this activation serves to dampen neuronal responses contributing to anxiety-like behavior. A growing body of evidence also shows that ethanol exposure alters brain endocannabinoid (eCB) levels and that chronic ethanol exposure induces persistent changes in the function of this system. We have recently observed that interstitial levels of the eCB substances anandamide and 2-arachidonoylglycerol (2-AG) are significantly decreased in the central nucleus of the amygdala (CeA) during acute withdrawal from chronic ethanol exposure. Moreover, resumption of ethanol intake restores 2-AG levels back to pre-withdrawal baseline levels. Based on the proposed role of eCBs as mediators of "anti-stress" effects, these findings suggest that deficient eCB signaling in the CeA may underlie a sensitized anxiety-like phenotype thought to contribute to excessive ethanol consumption. The experiments proposed in this Component will employ in vivo neurochemical monitoring and behavioral pharmacology to characterize the potential involvement of deficient eCB signaling in the CeA in the motivational effects of ethanol withdrawal. Experiments in the first Specific Aim will characterize the effect of ethanol dependence and withdrawal on basal and stress-induced eCB function in the CeA using in vivo microdialysis. Experiments in the second Specific Aim will utilize behavioral testing to characterize the involvement of altered eCB function in the CeA in the increased anxiety-like behavior and excessive ethanol consumption observed in ethanol-dependent rats. The proposed experiments will evaluate interactions between eCBs, GABA and glutamate in the CeA and therefore this work is highly related to the work proposed in the Cellular Neurobiology Research Component (Roberto/Siggins). The results obtained in this research component may provide important new insight into the neural mechanisms that propel alcohol addiction.