Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates

Abstract

We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.

Advances in the treatment of anxiety: Targeting glutamate

“…Many new theories and compounds have been proposed, including those based on 5-HT 1A agonists 10 and other specific serotonin-based compounds, 30,31 NK-1 antagonists and other Substance P-related species, 28 neuropeptides (NPY, NPS), 29,32 more specific GABA A agonists, 33,34 CRF antagonists, 35,36 glutamate modulators, and ␤-blockers, 37,38 among others.…”

Effects of Low- and High-Nicotine Cigarette Smoking on Mood States and the HPA Axis in Men

“…cocaine self-administration by rats, with minimal effects on food-maintained responding (Goeders and Guerin, 2000). CRH antagonists are also associated with alleviation of stress-induced anxiety (Habib et al, 2000;Ayala et al, 2004). Yet, in rhesus monkeys, with normal glucocorticoid levels, drug-induced increases in ACTH did not appear necessary to maintain cocaine self-administration (Broadbear et al, 1999a, b).…”

Integration of in vivo and in vitro approaches to characterize the toxicity of Antalarmin, a corticotropin-releasing hormone receptor antagonist

“…Efficacy studies performed in the rhesus monkey demonstrate that desirable pharmacologic activity (inhibition of fear and anxiety) can be achieved with a single oral dose of Antalarmin at 240 mg/m 2 (Habib et al, 2000). Although this pharmacologically effective dose approximates or exceeds the NOAEL identified in both rats (300 mg/m 2 /day on a 14-day schedule) and dogs (80 mg/m 2 /day on a 90-day schedule) in the present studies, it is below the MTD for Antalarmin in both species.…”

“…Furthermore, Antalarmin is orally bioavailable, and appears to provide a long duration of pharmacologic action in vivo (Webster et al, 1996). In rats, administration of Antalarmin suppresses the release of ACTH (Plotsky, 1997;Webster et al, 1996), and in primates, Antalarmin can attenuate the behavioral, neuroendocrine, and autonomic responses to stress (Deak et al, 1999;Habib et al, 2000;Ayala et al, 2004). On the basis of its activity in experimental model systems, Antalarmin is being developed as a model CRH receptor antagonist for possible clinical evaluation.…”