Driving the Downward Spiral: Alcohol-Induced Dysregulation of Extended Amygdala Circuits and Negative Affect.

Alcohol use disorder (AUD) afflicts a large number of individuals, families, and communities globally. Affective disturbances, including stress, depression, and anxiety, are highly comorbid with AUD, contributing in some cases to initial alcohol use and continued use. Negative affect has a particularly strong influence on the withdrawal/abstinence stage of addiction as individuals with AUD frequently report stressful events, depression, and anxiety as key factors for relapse. Treatment options for negative affect associated with AUD are limited and often ineffective, highlighting the pressing need for preclinical studies examining the underlying neural circuitry driving AUD-associated negative affect. The extended amygdala (EA) is a set of brain areas collectively involved in generating and regulating affect, and extensive research has defined a critical role for the EA in all facets of substance use disorder. Here, we review the expansive historical literature examining the effects of ethanol exposure on the EA, with an emphasis on the complex EA neural circuitry driving negative affect in all phases of the alcohol addiction cycle. Specifically, this review focuses on the effects of alcohol exposure on the neural circuitry in 2 key components of the EA, the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Additionally, future directions are proposed to advance our understanding of the relationship between AUD-associated negative affect and neural circuitry in the EA, with the long-term goal of developing better diagnostic tools and new pharmacological targets aimed at treating negative affect in AUD. The concepts detailed here will serve as the foundation for a companion review focusing on the potential for the endogenous cannabinoid system in the EA as a novel target for treating the stress, anxiety, and negative emotional state driving AUD.