Central Vasopressin VIA Receptor Blockade Impedes Hypothalamic-Pituitary-Adrenal Habituation to Repeated Restraint Stress Exposure in Adult Male Rats

Previous studies suggest that central arginine vasopressin (AVP) signaling can inhibit the hypothalamic-pituitary-adrenal (HPA) axis. To test a role for the AVP VIA receptor in stress HPA axis habituation, adult male rats were exposed to 5 consecutive days of 3 h restraint with or without continuous intracerebroventricular infusion of the VIA receptor antagonist d(CH2)5Tyr(Me)AVP (10 mu g/day). Assessment of neuropeptide expression and HPA output under basal conditions revealed no effects of VIA receptor antagonism in stress naive animals. Between the first and last day of restraint exposure, controls showed marked declines in ACTH and corticosterone responses, and maintained plasma concentrations of testosterone. In contrast, VIA receptor antagonized animals displayed significantly smaller declines in ACTH and corticosterone responses, and a decrease in plasma testosterone. Despite their reduced expression of HPA axis habituation, antagonized animals continued to show stress-induced increases in AVP mRNA in the hypothalamic paraventricular nucleus and bed nucleus of the stria terminalis, and even higher levels of AVP expression in the medial amygdala relative to controls. The data leave open the nature and extent to which these and other AVP-containing pathways are recruited during repeated restraint, but nevertheless reveal a critical role for central VIA receptors in stress adaptation. As the effects of VIA receptor antagonism were restricted to the repeated restraint condition, we conclude that normal adaptation to stress involves a shift toward enhanced AVP utilization and/or VIA receptor signaling. Neuropsychopharmacology (2012) 37, 2712-2719; doi:10.1038/npp.2012.136; published online 25 July 2012