Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior

• Published in: Molecular psychiatry Vol. 13; no. 11; pp. 1028 - 1042
• Main Authors: Lu, A, Steiner, M A, Whittle, N, Vogl, A M, Walser, S M, Ableitner, M, Refojo, D, Ekker, M, Rubenstein, J L, Stalla, G K, Singewald, N, Holsboer, F, Wotjak, C T, Wurst, W, Deussing, J M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2008; Nature Publishing Group
• Subjects: Acute effects; Adaptation, Psychological - drug effects; Adaptation, Psychological - physiology; Adult and adolescent clinical studies; Affective disorders; Analysis of Variance; Animal models; Animals; Behavior; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Brain Chemistry - drug effects; Care and treatment; Central nervous system; Central Nervous System - anatomy & histology; Central Nervous System - drug effects; Central Nervous System - metabolism; Coping; Coping behavior; Corticotropin releasing hormone; Corticotropin-Releasing Hormone - antagonists & inhibitors; Corticotropin-Releasing Hormone - genetics; Corticotropin-Releasing Hormone - metabolism; Depression; Depression, Mental; Exploratory Behavior; Female; Fenclonine - administration & dosage; Fenclonine - analogs & derivatives; Forebrain; Genetic aspects; Hindlimb Suspension; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - metabolism; Intermediate Filament Proteins - genetics; Male; Medical sciences; Medicine; Medicine & Public Health; Methyltyrosines - administration & dosage; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Mood disorders; Nerve Tissue Proteins - genetics; Nervous system; Nestin; Neurosciences; Norepinephrine; original-article; Pharmacotherapy; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Proteins - genetics; Psychiatry; Psychological aspects; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Pyrazoles - pharmacology; Radioimmunoassay - methods; Receptors, Corticotropin-Releasing Hormone - genetics; Receptors, Corticotropin-Releasing Hormone - metabolism; RNA, Untranslated; Stress; Stress, Physiological - genetics; Stress, Psychological - drug therapy; Stress, Psychological - etiology; Stress, Psychological - genetics; Swimming; Transgenic animals; Transgenic mice; Triazines - pharmacology; Germany; United States > US; corticotropin-releasing hormone; ROSA26; HPA axis; depression; DMP696; forced swim test; Mood disorder; Hypothalamohypophysoadrenal axis; Rodentia; Corticotropin releasing factor; Depression; Stress; Hypothalamic hormone; Vertebrata; Mammalia; Mouse; Animal; Behavior; Coping; Mutation; Hormone releasing factor
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2008.51

Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.