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.

项目摘要酒精使用障碍（AUD）是一个严重的公共健康问题，影响了约1510万美国成年人，或过去一个月饮酒的人中有11％。有几种可能增加的危险因素患有酒精使用障碍的风险，例如合并后创伤后应激障碍（PTSD）属性的风险增加了3倍。了解PTSD的知识存在很大的差距与AUD有关，部分原因是动物模型相对较新。在我们的实验室中，我们发现接触捕食者气味（PO）2,5-二氢-2,4,5-三甲基噻唑啉（TMT）对PO产生持久的反应性暴露环境，PO背景重新曝光后焦虑状行为升高，并增加酒精自我 PO暴露后一个月的管理，表明PO暴露可能是一个有前途的模型研究合并PTSD和AUD。为了奠定基础，以理解这些重叠疾病，该项目将重点关注压力和酒精文献中的新兴目标，矿物皮质激素受体（MR）。已经表明，先生调解了情境恐惧的发展在约束应力后，调节和MR表达在杏仁核中下调，两个模型与PTSD有关。此外，最近的研究表明，较低的MR基因表达与具有饮酒史的大鼠和猴子的饮酒和焦虑行为更大。目的 1个拟议的工作试图了解PO暴露后MR是否失调，以及是否这样失调的基础是酒精自我给药，寻求和重新定型的抬高行政。 MR失调将通过分析血浆醛固酮以及MR蛋白质和基因来评估。 ELISA，Western blot和QRT-PCR的PO暴露大鼠表达。分析更改 MR在饮酒中的功能作用，PO暴露的大鼠将接受自助酒精的训练并接受 MR拮抗剂螺内酯在进行自我管理会议之前或在寻求/重新定局之前禁欲后的行政会议。这项工作的目标2试图了解MR信号是否必不可少为了发展PO暴露的长期影响，其中大脑区域MR介导了神经元对PO暴露的反应。 MR拮抗剂螺内酯将在捕食者气味之前给大鼠施用暴露和大鼠将要么被分析以焦虑行为，酒精自我给药的抬高，如我们的初步研究中所述，寻求和重新启动自我管理或牺牲了90分钟后来检查了早期基因c-fos的脑区域表达。共同完成这些 AIMS将建立MR作为创伤压力与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合并条件并开发新的药物治疗。