Regulation of the mammalian response to stress is critical for life: instrumental to this response are the synergistic actions of two neurohormones, corticotrophin-releasing hormone (CRH) and vasopressin (VP). Following an acute stress event CRH and VP initiate the release of ACTH from the pituitary, which culminates in the secretion of corticosterone/cortisol into the peripheral circulation. We have established V1b receptor (R) knock-out (KO) mice to examine the consequences of a lack of vasopressin activity on pituitary corticotrophs. The specific hypothesis behind our research is that the pituitary V1b R is a very important regulator of the HPA axis response to acute stress. Plasma ACTH levels in response to acute stressors (novel environment (NE): exposure to clean cages for 30 min and; forced swim (FS): 5 min in 15cmH₂0 at 22°C – all animals (n=7) were killed immediately after each stress) were significantly reduced (~39% and 60% for NE and FS, respectively) in the V1b R KO animals when compared with their wild-type counterparts (NE: P<0.001, 114.53 ± 11.23 pg/ml, 301.88 ± 56.54 pg/ml; FS: P<0.001, 23.42 ± 3.02 pg/ml, 54.21 ± 8.29 pg/ml). Previous work in rodents has suggested that VP has a role in maintaining HPA axis tone in times of chronic stress (Ma et al 1999). Our chronic forced swim (CFS) and change in environment (CE) tests produced a diminished plasma ACTH response only in the mutant mice (CFS: P<0.001, 62.06 ± 22.24 pg/ml, 240.56 ± 28.71 pg/ml; CE: P0.05) These data suggest that the lack of habituation of corticosterone in response to chronic stress may involve other neuromodulators (e.g. cytokines), although VP and its cognate receptor may have a prominent role in maintaining pituitary (ACTH) responsiveness to both acute and chronic stressors.