Corticotropin-releasing hormone antagonists, astressin B and antalarmin: Differing profiles of activity in rhesus monkeys

Jillian H. Broadbear, Gail Winger, Jean E. Rivier, Kenner C. Rice, James H. Woods

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The present study compares the activity of two chemically distinct corticotropin-releasing hormone (CRH) antagonists at the level of the pituitary gland in rhesus monkeys, using exogenous CRH-stimulated increases in adrenocorticotropin (ACTH) and cortisol. Of chief interest was whether the CRH-R1-selective pyrrolopyrimidine, antalarmin, shown previously to have activity in the central nervous system (CNS), would differ in its antagonist profile from the CRH-R1- & 2-selective peptide, astressin B, which is unlikely to have access to the CNS following systemic administration. Nine rhesus monkeys (eight male), each with an indwelling venous catheter, were subjects in this study. Astressin B (0.001, 0.003, 0.03, 0.1, and 0.3 mg/kg) or antalarmin (1.0, 3.2, and 10 mg/kg) was administered as an intravenous (i.v.) pretreatment 15 min prior to administration of 1 or 10 μg/kg i.v. CRH. Antalarmin (10 mg/kg) was also administered alone on six occasions and its effects on behavior as well as on ACTH and cortisol levels were measured. Astressin B was assessed following i.v. and intracisternal (i.e.) administration. Astressin B dose-dependently abolished the CRH-stimulated ACTH and cortisol responses, with an antagonist effect lasting in excess of 24 h. Astressin B was approximately 300-times more potent when given i.c. than when it was administered via the i.v. route. By contrast, antalarmin antagonized the effects of CRH on ACTH but not cortisol at 1.0 and 3.2 mg/kg. At a larger dose, antalarmin stimulated ACTH and cortisol release and produced behavioral sedation. These latter effects diminished with repeated administration of antalarmin. The differences between astressin B and antalarmin may be due either to non-CRH receptor-mediated effects of antalarmin or to a complex interaction of antalarmin's effects at both central and peripheral CRH receptors.

Original languageEnglish (US)
Pages (from-to)1112-1121
Number of pages10
JournalNeuropsychopharmacology
Volume29
Issue number6
DOIs
StatePublished - Jun 2004

Keywords

  • ACTH
  • Antalarmin
  • Astressin B
  • CRH antagonist
  • Cortisol
  • Rhesus monkey (Macaca mulatta)

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'Corticotropin-releasing hormone antagonists, astressin B and antalarmin: Differing profiles of activity in rhesus monkeys'. Together they form a unique fingerprint.

Cite this