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）：压力和焦虑是有助于我们社会中酒精中毒的两个因素。 Stria末端（BNST）的床核是大脑的一个区域，其中奖励电路和应力途径会融合，并且已经证明乙醇会增加FOS活性。此外，BNST由肾上腺素能传入严重支配，这些传入与应力诱导的恢复药物寻求剂的行为范式有关。这些传入在长期的心理压力条件下通过阿拉德肾上能受体（CH-AR）调节HPA轴。此外，最近已经表明，在乙醇依赖的动物中抗衡ater虫的动物会减弱自我管理。我最近描述了谷氨酸能输入的长期抑郁症（LTD）到BNST中，该输入是由Qi-AR激活介导的。使用电生理，遗传学和药理方法，我将表征ARAR-LTD（AIM 1）并研究突触维护机制，通过该机制，CH-AR的激活产生了LTD（AIM 2）。此外，我将检验以下假设：Arar-LTD在体内被激活的动物在慢性间歇性乙醇暴露（CIE）的动物中被体内激活，并且该功能在功能上会改变HPA轴的输出和焦虑（AIM 3）。酒精滥用每年损失的工资，医疗保健，监狱/机构和其他社会经济成本每年损失超过十亿美元。压力和焦虑是已知影响饮酒行为的两个因素，通常可以在上瘾的状态下有助于消费。因此，对社会有益于对压力和焦虑如何影响酒精中毒的大脑，从而找到疗法的药理靶标，以阻止这种可怕的痛苦的进展。