The interactions of alcohol, sex, and stress

Human history is deeply intertwined with alcohol consumption. While alcohol use disorders (AUD) are often considered on an individual level they represent a societal problem, with increasing evidence for a dichotomy between men and women in their sequelae. It is known that stress impacts all aspects of the addiction cycle and while much work has been focused on the acute use of ethanol or withdrawal, many questions still remain about the transition to dependence and variation between sexes. This study sought to evolve our understanding of the changes occurring within the context of chronic ethanol exposure, as this is an area of investigation poised to significantly impact treatment paradigms. In chapter 2, preclinical studies were performed to elucidate the activation changes occurring in the stress responsive central nucleus of the amygdala (CeA) within chronic ethanol exposure on both a long term and short term scale, and to examine the effect of this chronic ethanol use on the stress response. Next, in chapter 3, anatomical approaches were utilized to link two major monoaminergic nuclei, the locus coeruleus (LC) and the dorsal raphe nucleus (DRN), by virtue of coordinate projections from the limbic stress nucleus, the CeA. The phenotype of these collateralized neurons was then identified as containing the key stress peptides corticotropin releasing factor (CRF) or dynorphin (DYN). Finally, in chapter 4, a molecular marker of the stress response, the CRFr, was examined in the LC using immunoelectron microscopy, and found to be dysregulated in a dichotomous fashion, potentially underlying some of the stress vulnerability seen in AUD. This study offers both molecular and circuitry targets that may be considered in future treatment paradigms, and highlights the importance of individualized treatment strategies for maximal patient benefit