Suppression of Adrenocorticotrophic Hormone Secretion by Simultaneous Antagonism of Vasopressin 1b and CRH-1 Receptors on Three Different Stress Models

Abstract

Background/Aims: Corticotrophin-releasing hormone (CRH), adrenocorticotrophic hormone (ACTH) and corticosterone are secreted during stress. These mediators may be involved in anxiety, depression and post-traumatic stress disorder, therefore antagonists have been developed to treat such conditions. Methods: The non-peptide CRH receptor type 1 antagonist CP154,526 and the vasopressin receptor type 1b antagonist SSR149415 were used to suppress the secretion of ACTH induced by ether exposure, forced swimming and restraint in adult male Wistar rats. Doses ranged from 3 to 60 mg/kg s.c. (controls with vehicle) alone or in combination, in varying time schedules to assess the duration and effectiveness of treatments. Results: Stressors increased plasma ACTH by 2.5- to 5-fold in control rats. SSR149415 at doses of 30 mg/kg was more effective at suppressing ACTH secretion after ether exposure and restraint but was ineffective against forced swimming. CP154,526 mildly affected ACTH rise after restraint at doses of 30 mg/kg. The combination of both antagonists at doses of 30 mg/kg effectively blocked the rise in plasma ACTH in all three stresses. The drug effects lasted less than 6 h. Conclusion: We demonstrated for the first time that simultaneous blockade of both vasopressin 1b and CRH-R1 receptors effectively abolish the ACTH response to physical and psychological stress modalities.