CRH receptor antagonism reverses the effect of social subordination upon central GABAA receptor binding in estradiol-treated ovariectomized female rhesus monkeys

• Type of Material: Article
• Authors: Vasiliki Michopoulos, Emory University; Molly Embree, Emory University; Kathy Reding, Emory University; Maria Sanchez, Emory University; Donna Toufexis, Emory University; John R Votaw, Emory University; Ronald Voll, Emory University; Mark Goodman, Emory University; Jean Rivier, Salk Institute for Biological Studies; Mark Wilson, Emory University; Sarah L. Berga, Wake Forest University
• Language: English
• Date: 2013-10-10
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 IBRO.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuroscience.2013.07.002
• Title of Journal or Parent Work: Neuroscience
• ISSN: 0306-4522
• Volume: 250
• Start Page: 300
• End Page: 308
• Grant/Funding Information: Portions of this work were supported by an investigator-initiated grant to SLB from Pfizer Pharmaceuticals Group to study hormones and brain.; The current study was supported by NIH HD046501 (MW), MH081816 (DT), DK026741 (JR); and in part OD P51OD011132.
• Keywords: social subordination; Neurosciences; Life Sciences & Biomedicine; GABAA receptor; flumazenil; MAJOR DEPRESSION; Neurosciences & Neurology; stress; CORTICOTROPIN-RELEASING HORMONE; PITUITARY-ADRENAL-FUNCTION; ASTRESSIN-B; astressin B; PARAVENTRICULAR NUCLEUS; SEROTONIN REUPTAKE TRANSPORTER; RAT-BRAIN; CEREBROSPINAL-FLUID; monkeys; Science & Technology; PARVOCELLULAR NEURONS; MESSENGER-RNA EXPRESSION
• Research Categories: Biology, Zoology; Biology, Neuroscience; Health Sciences, Mental Health

Abstract

Persistent exposure to environmental stressors causes dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and alters GABAA receptor (GABAAR) levels throughout the brain. Social subordination in socially housed female rhesus results in distinctive stress-related physiological and behavioral phenotypes that are dependent on the ovarian hormone estradiol (E2). In the present study, we utilized ovariectomized adult female rhesus monkeys undergoing hormone replacement with E2 to test the hypothesis that the chronic psychosocial stress of subordination alters GABAAR binding potential (GABAAR BPND) in limbic regions implicated in emotional processing including the prefrontal cortex, temporal lobe (amygdala and hippocampus), and hypothalamus. Furthermore, we tested the hypothesis that peripheral administration of a corticotropin-releasing hormone (CRH) receptor antagonist (astressin B) would reverse the alterations in GABAAR binding within these regions in subordinate females. After subjects received astressin B or saline for three consecutive days, GABAAR BPND was determined by positron emission tomography (PET) using 18F-flumazenil as a radioligand. T1-weighted structural magnetic resonance imaging scans were also acquired for PET scan co-registration, in order to perform a region of interest analysis using the pons as a reference region. Compared to socially dominant females, subordinate females exhibited increased GABAAR BPND in the prefrontal cortex but not in the temporal lobe or the hypothalamus. Administration of astressin B eliminated the status difference in GABAAR BPND in the prefrontal cortex, suggesting that the chronic stressor of social subordination modulates GABAergic tone via effects on CRH and the LHPA axis, at least in prefrontal regions.