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

项目总结 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 患上酒精使用障碍的风险，如共病的创伤后应激障碍(PTSD) 导致发生AUD的风险增加3倍。对于创伤后应激障碍是如何发生的，人们的认识存在显著差距 与急性尿毒症有关，部分原因是这种疾病的动物模型相对较新。在我们的实验室里，我们发现接触到 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环境重新暴露后焦虑样行为增加，以及酒精自我增加 在PO暴露后一个月以上给药，表明PO暴露可能是一种有前途的模式 研究并存的创伤后应激障碍和澳大利亚疾病。为了为理解它们之间的重叠奠定基础 这个项目将聚焦于压力和酒精文献中的一个新兴目标，即 盐皮质激素受体(MR)。已有研究表明，认知障碍在情境恐惧的发展中起中介作用 条件反射，束缚应激后杏仁核MR表达下调，两种模型 与创伤后应激障碍有关。此外，最近的研究表明，较低的MR基因表达与 有饮酒史的大鼠和猴子有更多的饮酒和焦虑行为。目标 一项拟议的工作试图了解在PO暴露后MR是否存在失调，以及如果这 调节失调是酒精自我管理、寻求和重新启动自我意识的基础 行政管理。MR失调将通过分析血浆醛固酮、MR蛋白和基因来评估 分别用ELISA法、Western印迹法和qRT-PCR法检测PO染毒大鼠肺组织中蛋白质的表达。来分析这些变化。 MR在饮酒中的作用，PO染毒大鼠将被训练自我给酒并接受 MR拮抗剂螺内酯在自我给药会话之前或在寻求/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试图了解MR信号是否是必要的 与PO暴露的长期效应的发展有关，以及在哪些脑区MR介导神经元 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注射 暴露和老鼠将被检测焦虑样行为的升高，酒精自我给药， 寻求并重新启动我们初步研究中描述的自我管理，或牺牲90分钟 随后检测脑区即刻早期基因c-Fos的表达。共同完成这些工作 AIMS将使MR成为创伤应激和饮酒升级之间的潜在桥梁， 这些知识可以用来进一步研究这些并存的情况，并开发新药 治疗。

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.