Vasopressin (VP) is the hormonal regulator of water homeostasis and has major effects on behaviour and vascular tone. In addition to this it is also a key regulator of the hypothalamic-pituitary-adrenal (HPA) axis, an action mediated through the G protein-coupled V1b receptor (R) (or V3R) predominantly found on the corticotrophs of the anterior pituitary. Although corticotrophin releasing hormone (CRH) seems to be the dominant adrenocorticotrophin (ACTH) secretagogue in rodents in response to acute stress (e.g. restraint), VP synergizes with CRH in activating the release of ACTH and may be preferentially released in response to some acute stressors (e.g. insulin-induced hypoglycaemia (1,2)). To further investigate the role of the VP V1bR in the HPA axis response to stress, we compared the effects of a recently described V1bR antagonist (Org 52186 (3)) on the levels of plasma ACTH and corticosterone (CORT) in V1bR knockout mice subjected to acute restraint stress. Org 52186 is a potent antagonist at the human V1bR and exhibits >1000-fold selectivity over the closely related V1a, V2 or oxytocin receptors. Adult male and female V1bR KO mice (and wild-type littermates) were administered s.c. with vehicle or Org 52186 (10 or 30mg/kg) 2h prior to acute restraint stress (30min in a 50ml ‘Falcon’ tube). Both doses of the V1bR antagonist significantly reduced stress-induced plasma ACTH and CORT levels in wild-type mice (ACTH: male wild-type restraint 129±16pg/ml, n=4, vs male wild-type restraint + Org52186 (30mg/kg) 45±7.87pg/ml, n=5; p<0.05). The HPA axis response to restraint was decreased in the V1bR KO (ACTH: male wild-type restraint 129±16pg/ml, n=4, vs male knockout + restraint 63±14pg/ml, n=5; p<0.001 – pretreatment with Org 52186 did not significantly effect the stress-induced hormone levels in these mice. Similar results were obtained in the female knockout and wild-type mice (e.g. vehicle + restraint 73±8pg/ml, n=7, vs Org 52186 (30mg/kg) + restraint 21±5.6pg/ml, n=6; p<0.001). In contrast to some previous studies on the VP-deficient Brattleboro rat (4), our studies clearly demonstrate that the V1bR is important for a normal acute restraint stress-induced ACTH and CORT response, and suggest that it is unlikely that possible compensatory/developmental changes resulting from the ablation of the V1bR gene play an important role in the HPA axis response to acute restraint in the V1bR KO.