Administration of high-dose ketoconazole, an inhibitor of steroid synthesis, prevents posttraumatic anxiety in an animal model. 2000

H Cohen, and J Benjamin, and Z Kaplan, and M Kotler
Ministry of Health, Beer-Sheva Mental Health Center, Anxiety and Stress Research Unit, P.O. 4600, Beer-Sheva, Israel. hagitc@bgumail.bgu.ac.il

Acute psychological stress is the presumed immediate cause of post-traumatic stress disorder (PTSD), and may also contribute to other anxiety disorders. Abnormal activity of the hypothalamic-pituitary-adrenal (HPA) axis has been tentatively implicated in some of the features of these disorders. Ketoconazole (KTCZ), an imidazole derivative, is a potent inhibitor of gonadal and adrenal steroidogenesis. The aim of this study was to explore the effects of KTCZ blockade of adrenal steroidogenesis, and consequent elevation of adreno-corticotropic hormone (ACTH), on a model of chronic post-traumatic anxiety in rats. Amelioration of anxious behaviors after reduction of corticosterone would suggest that corticosterone (and by implication cortisol in humans) is an important mediator of anxious symptoms: exacerbation of such behaviors would suggest that corticosterone elevations are only secondary, and possibly implicate corticotropin releasing hormone (CRH) and/or ACTH in the pathogenesis of anxious symptoms. We exposed rats for 10 min to cat scent, a prima facie valid model for acute psychological stress, with and without high dose KTCZ for 14 days. Treatment with KTCZ abolished the chronic behavioral effects of acute exposure to a cat scent. Lower levels of anxious behavior in KTCZ-treated and exposed rats were accompanied by lower plasma corticosterone, ACTH and prolactin (PRL) levels compared to untreated exposed rats. Results in this model implicate corticosterone, but not ACTH, in the pathogenesis of chronic anxiety following acute psychological stress.

UI MeSH Term Description Entries
D007654 Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Nizoral,R-41400,R41,400,R41400,R 41400
D008297 Male Males
D011597 Psychomotor Performance The coordination of a sensory or ideational (cognitive) process and a motor activity. Perceptual Motor Performance,Sensory Motor Performance,Visual Motor Coordination,Coordination, Visual Motor,Coordinations, Visual Motor,Motor Coordination, Visual,Motor Coordinations, Visual,Motor Performance, Perceptual,Motor Performance, Sensory,Motor Performances, Perceptual,Motor Performances, Sensory,Perceptual Motor Performances,Performance, Perceptual Motor,Performance, Psychomotor,Performance, Sensory Motor,Performances, Perceptual Motor,Performances, Psychomotor,Performances, Sensory Motor,Psychomotor Performances,Sensory Motor Performances,Visual Motor Coordinations
D001835 Body Weight The mass or quantity of heaviness of an individual. It is expressed by units of pounds or kilograms. Body Weights,Weight, Body,Weights, Body
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004702 Endocrine Glands Ductless glands that secrete HORMONES directly into the BLOOD CIRCULATION. These hormones influence the METABOLISM and other functions of cells in the body. Endocrine Gland,Gland, Endocrine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001007 Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with ANXIETY DISORDERS. Angst,Anxiousness,Hypervigilance,Nervousness,Social Anxiety,Anxieties, Social,Anxiety, Social,Social Anxieties
D013256 Steroids A group of polycyclic compounds closely related biochemically to TERPENES. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (STEROLS), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. (From Hawley's Condensed Chemical Dictionary, 11th ed) Steroid,Catatoxic Steroids,Steroids, Catatoxic
D013313 Stress Disorders, Post-Traumatic A class of traumatic stress disorders with symptoms that last more than one month. Moral Injury,Neuroses, Post-Traumatic,PTSD,Post Traumatic Stress Disorder,Post-Traumatic Stress Disorders,Acute Post-Traumatic Stress Disorder,Chronic Post-Traumatic Stress Disorder,Delayed Onset Post-Traumatic Stress Disorder,Neuroses, Posttraumatic,Posttraumatic Stress Disorders,Stress Disorder, Post Traumatic,Stress Disorders, Posttraumatic,Acute Post Traumatic Stress Disorder,Chronic Post Traumatic Stress Disorder,Delayed Onset Post Traumatic Stress Disorder,Injury, Moral,Moral Injuries,Neuroses, Post Traumatic,Post Traumatic Stress Disorders,Post-Traumatic Neuroses,Post-Traumatic Stress Disorder,Posttraumatic Neuroses,Posttraumatic Stress Disorder,Stress Disorder, Post-Traumatic,Stress Disorder, Posttraumatic

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