Predator odor stress and mineralocorticoid receptor regulation of alcohol self-administration

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 AUD, 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 AUD, in part because animal models for this are relatively new. This dissertation characterizes exposure to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) prior to alcohol self-administration as a model of stress-induced increases in alcohol self-administration. Male rats exposed to TMT show no changes in anxiety-like behavior or hyperarousal, but do show increased alcohol self-administration and reduced basolateral amygdala (BLA) response to alcohol. In order to lay groundwork for understanding the overlap between these disorders, this dissertation next explores the functional role of 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 single prolonged stress, two models relevant to PTSD. Recent studies have also shown that lower central amygdala (CeA) MR gene expression is associated with greater alcohol drinking and anxiety behaviors in rats and monkeys with a history of alcohol consumption. Thus MR may be a mediator of stress-induced increases in alcohol self-administration. Following TMT exposure, MR is upregulated in the CeA of male rats and dorsal hippocampus (dHC) of female, though only male rats show increases in alcohol self-administration. Finally, given that evidence linking CeA MR to alcohol drinking is only correlative, this dissertation probed the functional role of MR in alcohol self-administration. Systemic administration of the MR antagonist spironolactone reduced alcohol self-administration in male and female rats, while intra-CeA but not intra-dHC infusion of the selective MR antagonist eplerenone reduced alcohol self-administration in female rats. Furthermore, antisense oligonucleotide knockdown of CeA MR transiently reduced alcohol self-administration in female rats. Together the experiments in this dissertation outline TMT exposure as an animal model to study comorbid PTSD and AUD, leverage this model to identify BLA hyporesponsiveness to alcohol and increased MR expression as TMT-induced neuroadaptations that may underlie increased alcohol drinking, and establish the functional role of CeA MR in regulating alcohol self-administration.Doctor of Philosoph