The mineralocorticoid receptor as a potential bridge between traumatic stress and increased alcohol consumption

盐皮质激素受体作为创伤应激和饮酒增加之间的潜在桥梁

基本信息

批准号：
9790885
负责人：
Viren Makhijani
金额：
$ 3.03万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-07 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9790885
关键词：
Abstinence Adult Affect Alcohol consumption Alcohols Aldosterone Amygdaloid structure Animal Model Anxiety Behavior Behavioral Biological Assay Brain Brain region Comorbidity Complex Development Disease Dose Enzyme-Linked Immunosorbent Assay Exposure to FOS gene Feces Female Foxes Gene Expression Glucocorticoid Receptor Goals Hippocampus (Brain)Histology Hormones Hour Immediate-Early Genes Immunohistochemistry Kidney Knowledge Literature Long-Term Effects Maintenance Mediating Mineralocorticoid Receptor Modeling Molecular Monkeys Neurons Neurosciences Odors Pathology Peripheral Phenotype Plasma Play Post-Traumatic Stress Disorders Public Health Quantitative Reverse Transcriptase PCR Rattus Receptor Signaling Recording of previous events Research Research Personnel Risk Risk Factors Role Running Self Administration Specificity Spironolactone Stress Sucrose System Techniques Testing Training Water Western Blotting Work alcohol comorbidity alcohol reinforcement alcohol seeking behavior alcohol use disorder alcohol use initiation anxiety-like behavior behavioral pharmacology brain tissue career conditioned fear experience experimental study field study male neuroadaptation novel therapeutics pre-clinical protein expression receptor receptor expression response restraint stress screening skills therapeutic target trauma exposure

项目摘要

PROJECT SUMMARY Alcohol use disorder (AUD) is a serious public health concern, affecting approximately 15.1 million US adults, or 11% of those that consumed alcohol within the past month. There are several risk factors that can increase the risk of developing an alcohol use disorder, such as comorbid post-traumatic stress disorder (PTSD) which attributes a 3-fold increase in risk of developing an AUD. There is a significant gap in knowledge of how PTSD relates to AUDs, in part because animal models for this are relatively new. In our lab we find that exposure to the predator odor (PO) 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) produces lasting reactivity to the PO exposure context, elevated anxiety-like behavior following PO context re-exposure, and increased alcohol self- administration over a month after PO exposure, suggesting that PO exposure may be a promising model to study comorbid PTSD and AUD. In order to lay groundwork for understanding the overlap between these disorders, this project will focus on an emerging target in both the stress and alcohol literature, the mineralocorticoid receptor (MR). It has been shown that MR mediates development of contextual fear conditioning, and MR expression in the amygdala is downregulated following restraint stress, two models relevant to PTSD. Additionally, recent studies have shown that lower MR gene expression is associated with greater alcohol drinking and anxiety behaviors in rats and monkeys with a history of alcohol consumption. Aim 1 of the proposed work seeks to understand if MR is dysregulated following PO exposure, and if this dysregulation underlies the elevations in alcohol self-administration, seeking, and re-initiation of self- administration. MR dysregulation will be assessed by analyzing plasma aldosterone, and MR protein and gene expression of PO exposed rats by ELISA, western blot, and qRT-PCR respectively. To assay changes in the functional role of MR in alcohol drinking, PO exposed rats will be trained to self-administer alcohol and receive the MR antagonist spironolactone prior to a self-administration session or prior to a seeking/re-initiation of self- administration session following abstinence. Aim 2 of this work seeks to understand if MR signaling is essential to the development of the long term effects of PO exposure, and in which brain regions MR mediates neuronal response to PO exposure. The MR antagonist spironolactone will be administered to rats prior to predator odor exposure and rats will either be assayed for the elevations in anxiety-like behavior, alcohol self-administration, seeking, and re-initiation of self-administration as described in our preliminary studies, or sacrificed 90 minutes later to examine brain regional expression of the immediate early gene c-Fos. Together, completion of these aims will establish the MR as a potential bridge between traumatic stress and escalations in alcohol drinking, and that knowledge can be used to further research these comorbid conditions and develop novel drug treatments.

项目概要酒精使用障碍 (AUD) 是一个严重的公共卫生问题，影响着大约 1510 万美国成年人，或 11% 的人在过去一个月内饮酒。有几个风险因素可能会增加患酒精使用障碍的风险，例如共病创伤后应激障碍 (PTSD) 归因于开发 AUD 的风险增加了 3 倍。对于创伤后应激障碍（PTSD）如何与澳元相关，部分原因是动物模型相对较新。在我们的实验室中，我们发现暴露于捕食者气味 (PO) 2,5-二氢-2,4,5-三甲基噻唑啉 (TMT) 与 PO 产生持久的反应性暴露环境、重新暴露 PO 环境后焦虑样行为增加以及酒精自我感觉增加 PO 暴露后一个月以上给药，表明 PO 暴露可能是一个有前途的模型研究共病 PTSD 和 AUD。为了为理解这些之间的重叠奠定基础疾病，该项目将重点关注压力和酒精文献中的一个新兴目标，即盐皮质激素受体（MR）。研究表明，MR 介导情境恐惧的发展条件作用，并且杏仁核中的 MR 表达在约束应激后下调，两个模型与创伤后应激障碍（PTSD）相关。此外，最近的研究表明，较低的 MR 基因表达与有饮酒史的老鼠和猴子有更多的饮酒和焦虑行为。目的拟议工作之一旨在了解 MR 是否在 PO 暴露后失调，以及这是否调节失调是酒精自我管理、寻求和重新启动自我管理水平升高的基础行政。通过分析血浆醛固酮、MR 蛋白和基因来评估 MR 失调分别通过 ELISA、western blot 和 qRT-PCR 检测 PO 暴露大鼠的表达。测定变化 MR 在饮酒中的功能作用，PO 暴露的大鼠将被训练自我饮酒并接受 MR拮抗剂螺内酯在自我给药之前或在寻求/重新启动自我治疗之前禁欲后的管理会议。这项工作的目标 2 旨在了解 MR 信号传输是否至关重要 PO 暴露的长期影响的发展，以及 MR 介导神经元的大脑区域对 PO 暴露的反应。 MR 拮抗剂螺内酯将在捕食者气味之前给予大鼠暴露和大鼠将被检测焦虑样行为、酒精自我管理、寻求并重新开始自我管理，如我们的初步研究中所述，或牺牲 90 分钟随后检查立即早期基因 c-Fos 的大脑区域表达。共同完成这些目标是将 MR 建立为创伤性应激和饮酒升级之间的潜在桥梁，这些知识可用于进一步研究这些共病并开发新药治疗。