Alpha-1-Adrenergic Receptor Mediated Long Term Depression in the BNST

描述（由申请人提供）：压力和焦虑是导致我们社会中酗酒盛行的两个因素。终纹床核（BNST）是大脑中奖赏回路和应激通路交汇的区域，已经证明乙醇能增加Fos的活性。此外，BNST受肾上腺素能事件的大量支配，这些肾上腺素能事件参与了应激诱导的药物寻求恢复的行为范式。这些传入事件在长期心理应激条件下通过肾上腺素能受体（ch-AR）调节下丘脑轴。此外，最近有研究表明，在经历戒断的乙醇依赖动物中，拮抗arAR会减弱自我给药。我最近描述了一种由Qi-AR激活介导的谷氨酸输入BNST的长期抑制（LTD）。利用电生理学、遗传学和药理学方法，我将描述arAR-LTD（目的1），并研究ch-AR激活产生LTD的突触维持机制（目的2）。此外，我将验证arAR-LTD在经历慢性间歇乙醇暴露（CIE）戒断的动物体内被激活的假设，并且这在功能上改变了下丘脑轴输出和焦虑（目的3）。酗酒每年给美利坚合众国造成的工资损失、医疗保健、监狱/机构和其他社会经济成本超过1000亿美元。压力和焦虑是影响饮酒行为的两个已知因素，通常会导致饮酒成瘾。因此，更深入地了解压力和焦虑如何影响酗酒者的大脑，从而找到药物治疗目标，阻止这种可怕痛苦的发展，对社会是有益的。

DESCRIPTION (provided by applicant): Stress and anxiety are two factors that contribute to the prevalence of alcoholism in our society. The bed nucleus of the stria terminalis (BNST) is a region of the brain where reward circuitry and stress pathways converge, and where it has been shown that ethanol increases Fos activity. Additionally, the BNST is heavily innervated by adrenergic afferents that are involved in behavioral paradigms of stress induced reinstatement of drug seeking. These afferents modulate the HPA axis via the aradrenergic receptor (ch-AR) under conditions of prolonged psychological stress. Furthermore, it has recently been shown that antagonizing the arAR in ethanol dependent animals experiencing withdrawal attenuates self administration. I have recently described a long term depression (LTD) of glutamatergic inputs into the BNST that is mediated by Qi-AR activation. Using electrophysiological, genetic and pharmacological approaches I will characterize arAR-LTD (Aim 1) and investigate the synaptic maintenance mechanism by which activation of the ch-AR produces LTD (Aim 2). Furthermore, I will test the hypothesis that arAR-LTD is activated in vivo in animals experiencing withdrawal from chronic intermittent ethanol exposure (CIE) and that this functionally alters HPA axis output and anxiety (Aim 3). Alcohol abuse costs the United States of America over one hundred billion of dollars annually in lost wages, health care, prison/institutional and other socio-economic costs. Stress and anxiety are two factors known to impact drinking behavior and can often contribute to consumption in an addicted state. It is beneficial to society, therefore, to gain a greater understanding of how stress and anxiety affect the brain of alcoholics and, thus, to find pharmacological targets for therapies to halt the progression of this terrible affliction.