Suppression of ACTH secretion by antagonists of Vasopressin 1b and CRF1 receptors on three different stress models

Adrenocorticotropin secretion is the main hormonal brain output of the HPA axis and triggers the secretion of corticosterone in order to maintain homeostasis after unpleasant physical or psychological situations. In this study we employed the CRF type 1 receptor antagonist CP154,526 (Pfizer) and the vasopressin type 1b receptor antagonist SSR149415 (Sanofi-Aventis) to suppress the rise in plasma ACTH induced by ether exposure for 1 minute, forced swimming for 5 minutes and constraint for 1 hour in adult male Wistar rats. These stresses increased plasma ACTH by 2.5–4 fold. Animals were injected with doses between 3 and 60mg/kg s.c. and i.p. of each drug (controls with vehicle) and also with combinations of the two drugs, in varying time schedules to assess the duration and effectiveness of the treatments. Results demonstrated that SSR149415 in doses of 30mg/kg was more effective at suppressing ACTH secretion after ether exposure and constraint but was ineffective against forced swimming. CP154,526 mildly affected the ACTH rise after constraint stress in doses of 30mg/kg. The combination of both antagonists at doses of 30mg/kg effectively blocked the rise in plasma ACTH in all three models of stress. This effect was completely reversed at the end of 12h and after 6h only moderate blockade was detected. Drug treatment endured less when injected i.p. and increasing the dose of CP154,526 to 60mg/kg did not improve. In conclusion we state that the simultaneous blockade of both vasopressin 1b and CRF-1 receptors effectively abolish the plasma ACTH response to stress while the blockade of only one of these receptors may not work as well.