Selective activation of the hypothalamic vasopressinelgic system in mice deficient for the corticotropin-releasing hormone receptor 1 is dependent onglucocorticoids

Deficiency of CRH receptor 1 (CRHR1) severely impairs the stress response o f the hypothalamic-pituitary-adrenocortical (HPA) system and reduces anxiet y-related behavior in mice. Intriguingly, in mice deficient for the CRHR1 ( Crhr1(-/-)), basal plasma levels of ACTH are normal, suggesting the presenc e of compensatory mechanisms for pituitary ACTH secretion. We therefore stu died the impact of the hypothalamic neuropeptides arginine vasopressin (AVP ) and oxytocin (OXT) on HPA system regulation in homozygous and heterozygou s Crhr1 mutants under basal and different stress conditions. Basal plasma A VP concentrations were significantly elevated in Crhr1(-/-) mice. AW messen ger RNA expression was increased in the paraventricular nucleus of Crhr1(-/ -) mutants together with a marked increase in AW-like immunoreactivity in t he median eminence. Administration of an AVP V-1-receptor antagonist signif icantly decreased basal plasma ACTH levels in mutant mice. After continuous treatment with corticosterone, plasma AVP levels in homozygous Crhr1(-/-) mice were indistinguishable from those in wild-type littermates, thus provi ding evidence that glucocorticoid deficiency is the major driving force beh ind compensatory activation of the vasopressinergic system in Crhr1(-/-) mi ce. Neither plasma OXT levels under several different conditions nor OXT me ssenger RNA expression in the paraventricular nucleus were different betwee n the genotypes. Taken together, our data reveal a selective compensatory a ctivation of the hypothalamic vasopressinergic, but not the oxytocinergic s ystem, to maintain basal ACTH secretion and HPA system activity in Crhr1(-/ -) mutants.