EXCESS CORTICOTROPIN-RELEASING HORMONE-BINDING PROTEIN IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN TRANSGENIC MICE

Corticotropin-releasing hormone (CRH) is the primary hypothalamic rele asing factor that mediates the mammalian stress response, The CRH-bind ing protein (CRH-BP) is secreted from corticotropes, the pituitary CRH target cells, suggesting that the CRH-BP may modulate hypothalamic-pi tuitary-adrenal (HPA) axis activity by preventing CRH receptor stimula tion, Transgenic mice were generated that constitutively express eleva ted levels of CRH-BP in the anterior pituitary gland, RNA and protein analyses confirmed the elevation of pituitary CRH-BP, Basal plasma con centrations of corticosterone and adrenocorticotropin hormone (ACTH) a re unchanged, and a normal pattern of increased corticosterone and ACT H was observed after restraint stress, However, CRH and vasopressin (A VP) mRNA levels in the transgenic mice are increased by 82 and 35%, re spectively, to compensate for the excess CRH-BP, consistent with the i dea that CRH-BP levels are important for homeostasis. The transgenic m ice exhibit increased activity in standard behavioral tests, and an al tered circadian pattern of food intake which may be due to transgene e xpression in the brain, Alterations in CRH and AVP in response to elev ated pituitary CRH-BP clearly demonstrate that regulation of CRH-BP is important in the function of the HPA axis.