title: Escitalopram alters gene expression and HPA axis reactivity in rats following chronic overexpression of corticotropin-releasing factor from the central amygdala.
abstract: We have previously demonstrated that viral-mediated overexpression of corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) reproduces many of the behavioral and endocrine consequences of chronic stress. The present experiment sought to determine whether administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram reverses the adverse effects of CeA CRF overexpression. In a 2×2 design, adult male rats received bilateral infusions of a control lentivirus or a lentivirus in which a portion of the CRF promoter is used to drive increased expression of CRF peptide. Four weeks later, rats were then implanted with an Alzet minipump to deliver vehicle or 10mg/kg/day escitalopram for a 4-week period of time. The defensive withdrawal (DW) test of anxiety and the sucrose-preference test (SPT) of anhedonia were performed both before and after pump implantation. Additional post-implant behavioral tests included the elevated plus maze (EPM) and social interaction (SI) test. Following completion of behavioral testing, the dexamethasone/CRF test was performed to assess HPA axis reactivity. Brains were collected and expression of HPA axis-relevant transcripts were measured using in situ hybridization. Amygdalar CRF overexpression increased anxiety-like behavior in the DW test at week eight, which was only partially prevented by escitalopram. In both CRF-overexpressing and control groups, escitalopram decreased hippocampal CRF expression while increasing hypothalamic and hippocampal expression of the glucocorticoid receptor (GR). These gene expression changes were associated with a significant decrease in HPA axis reactivity in rats treated with escitalopram. Interestingly, escitalopram increased the rate of weight gain only in rats overexpressing CRF. Overall these data support our hypothesis that amygdalar CRF is critical in anxiety-like behavior; because the antidepressant was unable to reverse behavioral manifestations of CeA CRF-OE. This may be a potential animal model to study treatment-resistant psychopathologies.
authors.affiliation: Psychiatry Department, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, United States. eimartin@ucsd.edu
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Flandreau
authors.forename: Chase H
authors.initials: CH
authors.lastname: Bourke
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.forename: Wylie W
authors.initials: WW
authors.lastname: Vale
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D015283:Citalopram / Q000494:pharmacology*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010912:Pituitary-Adrenal Function Tests / Q000379:methods; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D015283:Citalopram; D003346:Corticotropin-Releasing Hormone; D003907:Dexamethasone; D011965:Receptors, Glucocorticoid; D017367:Selective Serotonin Reuptake Inhibitors