Abstract
A significant amount of neurobiological research regarding the development of alcohol use disorders (AUDs) has focused on alcohol-related activation and long-term alterations in the mesocortical dopaminergic reward pathways. However, alcohol does not only interact with brain reward systems. Many of its acute and chronic effects may be related to allostatic adaptations in hypothalamic and extrahypothalamic stress regulation pathways. For example, acute binge intoxication is associated with hypothalamically driven increases in blood cortisol, norepinephrine, and sex steroid metabolite levels. This may contribute to the development of mesocortical sensitization to alcohol. Furthermore, chronic alcohol exposure is associated with systemic dysregulation of the hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and sex steroid systems. This dysregulation appears to manifest as neuroendocrine tolerance. In this review, we first summarize the literature suggesting that alcohol-induced alterations in these hypothalamic systems influence craving and contribute to the development of AUDs. We note that for women, the effects of alcohol on these neuroendocrine stress regulation systems may be influenced by the rhythmic variations of hormones and steroids across the menstrual cycle. Second, we discuss how changes in these systems may indicate progression of AUDs and increased risk of relapse in both sexes. Specifically, neuroendocrine tolerance may contribute to mesocortical sensitization, which in turn may lead to decreased prefrontal inhibitory control of the dopaminergic reward and hypothalamic stress systems. Thus, pharmacological strategies that counteract alcohol-associated changes in hypothalamic and extrahypothalamic stress regulation pathways may slow the development and progression of AUDs.