Alcohol-induced dysregulation of stress-related circuitry: The search for novel targets and implications for interventions across the sexes

Abstract

While the ability to process fermented fruits and alcohols was once an adaptive trait that improved nutrition and quality of life, the availability and prevalence of high potency alcoholic drinks has contributed to alcohol abuse disorders in a vulnerable portion of the population. Although the neural reward systems take part in the initial response to alcohol, negative reinforcement and stress, which are normally adaptive responses, can intersect to promote continued alcohol use at all stages of the addiction cycle. Eventually a point is reached where these once adaptive responses become dysregulated resulting in uncontrolled intake that constitutes a clinically important condition termed alcohol use disorder (AUD). Current research is targeted at both the behavioral and molecular adaptations in AUDs in an effort to better develop novel approaches to intervention. In this review, historical context is provided demonstrating the societal burden of alcohol use and abuse disorders. The importance of gender in the mechanism of action of alcohol is discussed. Finally, the impact of alcohol on stress-related circuitry, uncovered by preclinical research, is outlined to provide insight into potential novel pharmacological approaches to the treatment of AUD.

Keywords: Alcohol use disorders; Central nucleus of the amygdala; Locus coeruleus; Sex differences.

Figure 1

Stress is known to impact every aspect of the addiction cycle. Stress and reward intersect to promote initial use of a substance, and stress promotes continued usage often leading to compulsive alcohol seeking behaviors. Physiological adaptations following alcohol exposure lead to dependence and discontinuing usage precipitates withdrawal. Withdrawal acts as a stressor and negative reinforcer, perpetuating the addiction cycle. Patients and treatment providers both point to stress as a source of relapse and a barrier to abstinence, as stressors can promote resumption of addictive behaviors many years after remission.

Figure 2

Action of alcohol exposure on the hypothalamic-pituitary-adrenal (HPA) axis. (Left) Acutely, alcohol decreases anxiety and promotes systemic release of glucocorticoids. (Right) Chronic alcohol exposure elicits increased anxiety, causes hypertrophy of the adrenal glands and blunting of the corticosterone feedback response.

Figure 3

(Top Left) The activity patterns of the CeA and LC are dysregulated after chronic ethanol exposure, with males showing a neuronal habituation to chronic use, and females showing a higher rate of activation at baseline. (Bottom Left) The stress activation response of the CeA is potentiated after chronic ethanol exposure in both sexes. In females, neuronal activity levels after a stressor are similar to those after chronic ethanol exposure, while males show differential activation patterns in ethanol-treated compared to control. (Top Right) The LC shows a sexually dimporphic response to chronic ethanol exposure with CRFr distribution patterns mimicking a stress response. Habituation is observed in males, while females do not show such neuronal adaptations.