Turning off the anxiety master switch.

Anxiety is a natural adaptive behavioral state controlled by specific neuronal circuits and endocrine systems that are activated by real or perceived danger. However, with the ever increasing pace of modern societies, prolonged and unnecessary anxiety has become a major problem for many people. Although neurotransmitter and neuroendocrine pathways that either stimulate or suppress anxiety pathways have been identified during the past three decades, resulting in the development of several drugs that can relieve anxiety, a recent flurry of studies on the neuro-peptide corticotropin-releasing hormone (CRH) has propelled a resurgence of excitement in the field of anxiety research. CRH was first identified as the neuropeptide produced by hypothalamic neurons, which is released into the portal vessels and stimulates production of adrenocorticotropin, an action critical for activation of the brain-hypothalamic-pituitary-adrenal (HPA) axis that controls production of glucocorticoids. However, CRH is also produced by neurons in several other regions of the brain, as are two different CRH receptors (CRHR-1 and CRHR-2) coupled to adenylate cyclase and cyclic AMP production. Studies in rodents had provided evidence that CRH plays an important role in activating anxiety pathways in the brain.Habib et al.1xOral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Habib, K.E. et al. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 6078–6084Crossref | Scopus (300)See all References1 report on the effects, in a primate model of psychosocial stress, of a highly specific antagonist of CRHR-1 called antalarmin. The authors characterized the pharmacokinetics of antalarmin in blood and brain after oral administration in rhesus macaques. They then performed a double-blind placebo-controlled study of the effects of antalarmin on behavioral and neuroendocrine responses to an acute psychosocial stress paradigm in which two monkeys unfamiliar with each other are placed in adjacent cages separated by a transparent plexiglass screen. Antilarmin inhibited an array of anxiety- and fear-related behaviors including grimacing, teeth gnashing, urination, body tremors and cage shaking. Monkeys given antalarmin exhibited sexual and exploratory behaviors normally inhibited by psychosocial stress. Moreover, antalarmin suppressed stress-induced increases in plasma levels of adrenocorticotropin, cortisol and epinephrine. The authors’ findings establish an essential role for CRH acting on CRHR-1 as a ‘master switch’ that triggers a complete psychological and endocrine anxiety response in primates. Interestingly, recent analyses of stress responses in CRHR-2 knockout mice suggest that CRHR-2, whose endogenous ligand might be urocortin rather than CRH, mediates a central anxiolytic response2xMice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Bale, T.L. et al. Nat. Genet. 2000; 24: 410–414Crossref | PubMed | Scopus (620)See all References, 3xDeletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Kishimoto, T. et al. Nat Genet. 2000; 24: 415–419Crossref | PubMed | Scopus (382)See all References. Thus, two highly homologous receptors linked to the same second messenger system serve opposite roles in stress responses, presumably as the result of selective activation by different ligands and/or differential cellular localization of the receptors.The implications of the powerful control of stress responses by CRH receptor signaling are profound. A variety of clinically important disorders might benefit from selective antagonism of CRHR-1 including not only anxiety and panic disorders, but also serious cardiovascular, reproductive and gastrointestinal disorders in which psychosocial stress plays a major role.