The relationship between stress and alcohol is complex, with a wide array of factors (genetic, biological, and environmental) playing a role in contributing to the outcome of stress-alcohol interactions. While stress may interact with alcohol during the initial stages of drinking to enhance its rewarding effects, persistent excessive alcohol consumption serves as a potent stressor itself, continually challenging and ultimately compromising the physiological integrity of the subject. Prolonged alcohol exposure leads to fundamental changes in brain reward and neuroendocrine/stress systems beyond normal homeostatic limits (i.e., a state of allostasis), which, in turn, impacts physiological and brain motivational systems that are integral to control and regulation of ethanol consumption. As reviewed in this article, substantial evidence has accrued demonstrating that chronic alcohol exposure produces profound dysregulation in the neuroendocrine (HPA axis) stress system while at the same time recruiting and sensitizing extra-hypothalamic stress circuitry in the brain. Use of animal (primarily rodent) models has been critical to advancing our understanding about how chronic alcohol-induced changes in neuroendocrine and brain stress systems, particularly those intertwined with reward circuitry, underlie expression of withdrawal
