Role of hypothalamic corticotropin-releasing factor in mediating alcohol-induced activation of the rat hypothalamic–pituitary–adrenal axis

• Alcohol stimulates hypothalamic CRF neurons, in particular through nitric oxide and catecholamines.
• Alcohol can act directly on the CRF gene, but not on pituitary corticotrophs.
• Endogenous CRF plays a major role in mediating the HPA axis response to alcohol.
• Prior exposure to alcohol blunts subsequent responses of the HPA axis to alcohol.
• The prior effect of alcohol can be long-lasting, even permanent.

Alcohol stimulates the hypothalamic–pituitary–adrenal (HPA) axis through brain-based mechanisms in which endogenous corticotropin-releasing factor (CRF) plays a major role. This review first discusses the evidence for this role, as well as the possible importance of intermediates such as vasopressin, nitric oxide and catecholamines. We then illustrate the long-term influence exerted by alcohol on the HPA axis, such as the ability of a first exposure to this drug during adolescence, to permanently blunt neuroendocrine responses to subsequent exposure of the drug. In view of the role played by CRF in addiction, it is likely that a better understanding of the mechanisms through which this drug stimulates the HPA axis may lead to the development of new therapies used in the treatment of alcohol abuse, including clinically relevant CRF antagonists.