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

点击翻译按钮获取中文摘要

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.