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The CRF1 Receptor, a Novel Target for the Treatment of Depression, Anxiety, and Stress-Related Disorders

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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 organism's 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.

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

Document Type: Research Article

Affiliations: Neurogen Corporation, 35 Northeast Industrial Road, Branford CT 06405, USA

Publication date: 01 June 2007

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  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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