title: A mixed glucocorticoid/mineralocorticoid receptor modulator dampens endocrine and hippocampal stress responsivity in male rats.
abstract: Aberrant glucocorticoid secretion is implicated in the pathophysiology of stress-related disorders (i.e., depression, anxiety). Glucocorticoids exert biological effects via mineralocorticoid (MR) and glucocorticoid (GR) receptors. Previous data from our laboratory indicate that GR antagonism/modulation (i.e., mifepristone, CORT 108297) regulate endocrine, behavioral, and central stress responses. Because of the dynamic interplay between MR and GR on HPA axis regulation and emotionality, compounds targeting both receptors are of interest for stress-related pathology. We investigated the effects of CORT 118335 (a dual selective GR modulator/MR antagonist) on endocrine, behavioral, and central (c-Fos) stress responses in male rats. Rats were treated for five days with CORT 118335, imipramine (positive control), or vehicle and exposed to restraint or forced swim stress (FST). CORT 118335 dampened corticosterone responses to both stressors, without a concomitant antidepressant-like effect in the FST. Imipramine decreased corticosterone responses to restraint stress; however, the antidepressant-like effect of imipramine in the FST was independent of circulating glucocorticoids. These findings indicate dissociation between endocrine and behavioral stress responses in the FST. CORT 118335 decreased c-Fos expression only in the CA1 division of the hippocampus. Imipramine decreased c-Fos expression in the basolateral amygdala and CA1 and CA3 divisions of the hippocampus. Overall, the data indicate differential effects of CORT 118335 and imipramine on stress-induced neuronal activity in various brain regions. The data also highlight a complex relationship between neuronal activation in stress and mood regulatory brain regions and the ensuing impact on endocrine and behavioral stress responses.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States; Neuroscience Graduate Program, University of Cincinnati College of Medicine, United States. Electronic address: nguyenee@mail.uc.edu.
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Nguyen
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Streicher
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Berman
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States.
authors.forename: Jody L
authors.initials: JL
authors.lastname: Caldwell
authors.affiliation: Experimental Psychology Graduate Program, University of Cincinnati, United States.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ghisays
authors.affiliation: Experimental Psychology Graduate Program, University of Cincinnati, United States.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Estrada
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States; Neuroscience Graduate Program, University of Cincinnati College of Medicine, United States.
authors.forename: Aynara C
authors.initials: AC
authors.lastname: Wulsin
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States; Neuroscience Graduate Program, University of Cincinnati College of Medicine, United States.
authors.forename: Matia B
authors.initials: MB
authors.lastname: Solomon
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003345:Corticosterone / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006728:Hormones / Q000494:pharmacology*; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013941:Thymine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C000606526:CORT118335; D006728:Hormones; D016760:Proto-Oncogene Proteins c-fos; D011619:Psychotropic Drugs; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D007099:Imipramine; D013941:Thymine; D003345:Corticosterone
keywords: Antidepressants; Depression-like behavior; Forced swim test; HPA-axis; Restraint; c-Fos