ABSTRACT
Corticotropin-releasing hormone (CRH) coordinates neuroendocrine and behavioral adaptations to stress. Acute CRH administration in vivo activates extracellular signal-regulated kinase 1/2 (ERK1/2) in limbic brain areas, acting through the CRH receptor type 1 (CRH-R1). In the present study, we used CRH-COE-Cam mice that overexpress CRH in limbic-restricted areas, to analyze the effect of chronic CRH overexpression on ERK1/2 activation. By immunohistochemistry and confocal microscopy analysis we found that pERK1/2 levels in the basolateral amygdala (BLA) were similar in control and CRH overexpressing mice under basal conditions. Acute stress caused comparably increased levels of corticosterone in both control (CRH-COEcon-Cam) and CRH overexpressing (CRH-COEhom-Cam) animals. CRH-COEhom-Cam mice after stress showed reduced pERK1/2 immunoreactivity in the BLA compared to CRH-COEhom-Cam animals under basal conditions. Radioligand binding and in situ hybridization revealed higher density of CRH-R1 in the amygdala of CRH-COEhom mice under basal conditions compared to control littermates. A significant reduction of the receptor levels was observed in this area after acute stress, suggesting that stress may trigger CRH-R1 internalization/downregulation in these CRH overexpressing mice. Chronic CRH overexpression leads to reduced ERK1/2 activation in response to acute stress in the BLA.
Subject(s)
Amygdala/enzymology , Corticotropin-Releasing Hormone/metabolism , Gene Expression Regulation, Enzymologic/physiology , Mitogen-Activated Protein Kinase 3/metabolism , Receptors, Corticotropin-Releasing Hormone/metabolism , Stress, Psychological/pathology , Amphibian Proteins/metabolism , Animals , Autoradiography , Corticosterone/blood , Corticotropin-Releasing Hormone/genetics , Disease Models, Animal , Gene Expression Regulation, Enzymologic/genetics , Iodine Isotopes/metabolism , Male , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinase 3/genetics , Peptide Hormones/metabolism , Protein Binding/genetics , Radioimmunoassay , Receptors, Corticotropin-Releasing Hormone/agonists , Restraint, Physical/methods , Stress, Psychological/enzymology , Stress, Psychological/etiology , Time FactorsSubject(s)
Central Nervous System/metabolism , Corticotropin-Releasing Hormone/metabolism , Disease Models, Animal , Stress, Psychological , Animals , Corticotropin-Releasing Hormone/genetics , Gene Expression Regulation/genetics , Integrases/genetics , Mice , Proteins/genetics , RNA, Untranslated , Stress, Psychological/genetics , Stress, Psychological/metabolism , Stress, Psychological/pathology , SwimmingABSTRACT
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.
