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流行的两个因素。终纹床核（BNST）是大脑的一个区域，奖励回路和压力通路会聚在这里，乙醇可以增加Fos活性。此外，BNST严重受肾上腺素能传入神经支配，肾上腺素能传入神经参与应激诱导的药物寻求恢复的行为范式。这些传入调节HPA轴通过肾上腺素能受体（ch-AR）的条件下，长期的心理压力。此外，最近已经表明，在经历戒断的乙醇依赖性动物中拮抗arAR会减弱自我给药。我最近描述了一种由Qi-AR激活介导的BNST中的多巴胺能输入的长期抑制（LTD）。使用电生理学，遗传学和药理学方法，我将表征arAR-LTD（目的1），并研究突触的维持机制，通过激活的ch-AR产生LTD（目的2）。此外，我将测试的假设，arAR-LTD在体内激活的动物经历退出慢性间歇性乙醇暴露（CIE），这在功能上改变HPA轴输出和焦虑（目标3）。酗酒使美利坚合众国每年损失1 000多亿美元的工资、保健、监狱/机构和其他社会经济费用。压力和焦虑是影响饮酒行为的两个因素，通常会导致成瘾状态下的消费。因此，更好地了解压力和焦虑如何影响酗酒者的大脑，从而找到治疗的药理学靶点，以阻止这种可怕的痛苦的发展，这对社会是有益的。

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.