Hypothalamic-pituitary-adrenocortical system and mood disorders: highlights from mutant mice

In recent years, refined molecular technologies and the generation of genetically engineered mice have allowed to specifically target individual genes involved in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Given the fundamental role of the corticotropin-releasing hormone (CRH) system in anxiety, stress-associated pathologies, and mood disorders, we describe genetic modifications of the genes that encode proteins integral to the CRH/CRH receptor system with particular emphasis on conditional gene-targeting strategies. The profile of results, consistent with current knowledge of CRH function from more traditional assays, indicates that enhancement of the CRH function is associated with an activation of the HPA system, an anxious phenotype, alterations in cognitive performance, reductions in food intake, and disturbances of autonomic functions. In general, blockade of CRH activity produces the opposite effects, namely an anxiety-reduced phenotype. Molecular genetic strategies for conditional inactivation or overexpression of the glucocorticoid receptor contribute to our understanding of the genetics of endocrine activity and behavior, the most complex form of biological organization. In addition, we introduce mice with a genetic manipulation in the function of the blood-brain barrier as an animal model for the study of neuroendocrine regulation and, in particular, of HPA system activity. By use of mice deficient for abcb1- (also called multidrug resistance gene 1, mdr1-) type P glycoproteins, it was shown most recently that abcb1-type P glycoproteins control the access of endogenous glucocorticoids into the central nervous system. Thus, the ABCB1-type P glycoprotein function exerts a profound influence on activity and regulation of the HPA system under both basal conditions and during stress. Taken together, these genetically engineered mice are valuable tools for increasing our understanding of HPA system dysregulation in anxiety and stress-related pathologies, including human affective disorders. The identification and detailed characterization of these molecular pathways will ultimately lead to the development of novel neuropharmacological intervention strategies.