Proteomic analysis of central amygdala systems regulated by mifepristone in the context of alcohol dependence

Abstract

Alcohol use disorder (AUD) is a psychiatric disorder characterized by escalated alcohol use and the emergence of negative affective symptoms. Studies have described a dysregulation of glucocorticoid receptor (GR) signaling in the context of AUD at the levels of the hypothalamic-pituitary-adrenal (HPA) axis and central amygdala (CeA). A functional increase in CeA GR activity occurs during alcohol withdrawal in alcohol-dependent animal models, and the GR antagonist mifepristone reduces alcohol-seeking and drinking behaviors in both rodents and humans. The aims of this study were to determine differential CeA protein expression in alcohol-dependent rats and examine the effects of mifepristone treatment in this context. Male and female Wistar rats were exposed to chronic intermittent ethanol vapor (CIEV) or air (control) for 10 weeks. In week 7, half of the animals in each group received either subcutaneous placebo pellets or mifepristone pellets. At the end of Week 10, the rats were euthanized during acute CIEV withdrawal (and identical time in control groups). The CeA was analyzed using discovery-based proteomics and Ingenuity Pathway Analysis (IPA). In males, among the 3050 proteins detected, 274 proteins were significantly altered by alcohol, and 158 of these proteins were normalized by mifepristone. In females, among the 2631 detected proteins, 37 proteins were altered by alcohol, and 13 of these proteins were normalized by mifepristone. Alcohol and mifepristone elicited sex-dependent alterations in protein expression within the CeA, confirming and extending previous research to highlight specific proteins and pathways as medication targets to offer novel therapeutic avenues for treating AUD.

Keywords: Alcohol dependence; Central amygdala; Glucocorticoid; Mifepristone; Proteomics.