Abstract

The present review focuses on the corticotropin releasing factor type 1 (CRF1) receptor as a novel target for treating depression, anxiety and other stress-related disorders. An organisms stress response system is a complex network of neuronal, endocrine and autonomic pathways which has evolved to provide adaptive reactions to severe environmental and physiological stressors. The peptide CRF plays a critical role in the proper functioning of the stress response system through its actions on CRF1 receptors located at multiple anatomical sites. Clinical data indicate that dysfunctions of the stress response system, expressed as excessive CRF activity and possible hyperstimulation of CRF1 receptors, are present in a range of stress-related disorders, including depression, anxiety, and irritable bowel syndrome. CRF1 dysfunction may be particularly prominent in severe forms of these disorders (e.g. melancholic or psychotic depression, comorbid conditions, chronic posttraumatic stress disorder) and/or when these disorders are accompanied by a history of exposure to early life trauma. Available clinical data support the potential therapeutic efficacy of pharmacological agents which block the CRF1 receptor. Preclinical studies demonstrate that CRF1 receptor antagonists are efficacious in animal models in which CRF pathways and CRF1 receptors are hyperactivated, whereas they tend to be quiescent in states of low basal CRF activity, indicative of potentially reduced side effects in humans. Symptom diversity in animal models of stress and in human stress disorders may result from dysfunctions in different CRF1 receptor populations and/or different functional states of the CRF1 receptor. Small molecule, orally-active CRF1 receptor antagonists may be a broadly useful approach for treating a range of stress-related disorders that are associated with excessive CRF1 receptor stimulation.

Keywords: glucocorticoids, Irritable Bowel Syndrome, Anxiety Models, posttraumatic stress disorder, hypothalamic-pituitary-adrenal (HPA) axis