Corticotropin-Releasing Hormone Antagonists, Astressin B and Antalarmin: Differing Profiles of Activity in Rhesus Monkeys

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 mg/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.c.) 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 receptormediated effects of antalarmin or to a complex interaction of antalarmin's effects at both central and peripheral CRH receptors.

Treatment with CRH‐1 antagonist antalarmin reduces behavioral and endocrine responses to social stressors in marmosets (Callithrix kuhlii)

“…Under the conditions in this experiment, acute treatment of marmosets with antalarmin influenced both the cascade of endocrine events in the HPA axis that culminates in the release of cortisol and the behavioral responses to a psychosocial stressor, in that behavioral indices of stress and agitation were reduced, as was the magnitude of the cortisol response. Acute pretreatment of macaques with antalarmin blocks the CRH-induced elevation in circulating ACTH and cortisol [Broadbear et al, 2004]. Acute treatment of male macaques with antalarmin likewise impacted both behavioral and endocrine endpoints during exposure to an intense social stressor--exposure to an unfamiliar conspecific.…”

“…Broadbear et al [2004] treated macaques with varying doses of antalarmin and anecdotally noted behavioral responses immediately following treatment. Animals receiving the highest doses (10 mg/kg, intravenously [i.v.])…”

“…CRH regulates HPA activity via its action on the CRH-1 receptor, since macaques pretreated with antalarmin show dose-dependent reductions in ACTH and cortisol levels following a standard CRH challenge [Broadbear et al, 2004]. Two recent studies have assessed the impact of antalarmin treatment on behavioral and endocrine responses to social stress in primates.…”

Antiglucocorticoids in psychiatry

“…These drugs are still in preclinical stages but preliminary results suggest that these CRH antagonists indeed have clinical potential (Broadbear 2004;French 2007). Other drug development programmes are targeting central CRH receptors that are further from the HPA axis.…”

Angiotensin II AT1 receptor antagonists inhibit the angiotensin‐CRF‐AVP axis and are potentially useful for the treatment of stress‐related and mood disorders

“…These are indicators of poor potency and efficacy, poor penetration through the blood-brain barrier, toxic potential, and reduced effects after chronic administration [Lin and Lu, 1997;Zorrilla and Koob, 2004]. Rhesus monkeys have been shown to self-administer the CRF 1 receptor antagonist antalarmin, indicative of addition potential [Broadbear et al, 2002[Broadbear et al, , 2004, and after long-term administration, some CRF 1 receptor antagonists exhibit a relatively high degree of ataxia and sedation [Zorrilla and Koob, 2004].…”