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

α-1-肾上腺素能受体介导 BNST 中的长期抑郁

• 批准号: 7333868
• 负责人: Zoe Anastasia McElligott
• 金额: $ 2.56万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7333868
• 关键词: AMPA Receptors; Acute; Adrenergic Agents; Affect; Alcohol abuse; Alcohol withdrawal syndrome; Alcoholism; Americas; Animals; Anxiety; Attenuated; Behavioral Paradigm; Brain; Brain region; Breathing; Chronic; Condition; Consumption; Corticosterone; Corticotropin; Data; Economics; Electrophysiology (science); Ethanol; Ethanol dependence; Genetic; Glutamates; HPSE gene; Healthcare; Hippocampus (Brain); Knockout Mice; Lateral; Long-Term Depression; Maintenance; Measurement; Mediating; Methods; Output; Pathway interactions; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Prevalence; Prisons; Property; Psychological Stress; Qi; Receptor Signaling; Recruitment Activity; Role; Self Administration; Signal Pathway; Slice; Societies; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; Techniques; Testing; United States; Visual Cortex; Wages; Withdrawal; adrenergic; alcohol exposure; alpha-1 adrenergic receptors; cost; drinking behavior; experience; hypothalamic-pituitary-adrenal axis; in vivo; problem drinker; receptor; reward circuitry

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.

描述（由申请人提供）：压力和焦虑是导致我们社会酗酒盛行的两个因素。终纹床核 (BNST) 是大脑中奖赏回路和压力通路汇聚的区域，并且已证明乙醇会增加 Fos 活性。此外，BNST 受到肾上腺素能传入神经的严重支配，这些传入神经参与压力诱导的药物寻求恢复的行为范式。在长期心理压力的情况下，这些传入神经通过阿拉肾上腺素能受体 (ch-AR) 调节 HPA 轴。此外，最近已经表明，在经历戒断的乙醇依赖动物中拮抗arAR会减弱自我给药。我最近描述了由 Qi-AR 激活介导的 BNST 谷氨酸输入的长期抑制 (LTD)。我将使用电生理学、遗传学和药理学方法来表征 arAR-LTD（目标 1），并研究 ch-AR 激活产生 LTD 的突触维持机制（目标 2）。此外，我将测试以下假设：arAR-LTD 在经历慢性间歇性乙醇暴露 (CIE) 戒断的动物体内被激活，并且这会在功能上改变 HPA 轴输出和焦虑（目标 3）。酗酒每年给美国造成超过一千亿美元的工资损失、医疗保健损失、监狱/机构损失和其他社会经济损失。压力和焦虑是已知影响饮酒行为的两个因素，并且通常会导致成瘾状态下的饮酒。因此，更好地了解压力和焦虑如何影响酗酒者的大脑，从而找到治疗方法的药理学靶点来阻止这种可怕的痛苦的进展，对社会是有益的。