title: Sensitization of the Hypothalamic-Pituitary-Adrenal Axis in a Male Rat Chronic Stress Model.
abstract: Stress activation of the hypothalamic-pituitary-adrenal (HPA) axis is regulated by rapid glucocorticoid negative feedback. Chronic unpredictable stress animal models recapitulate certain aspects of major depression in humans, which have been attributed to impaired glucocorticoid negative feedback. We tested for an attenuated HPA sensitivity to fast glucocorticoid feedback inhibition in male rats exposed to a chronic variable stress (CVS) paradigm. In vitro, parvocellular neuroendocrine cells of the hypothalamic paraventricular nucleus recorded in slices from CVS rats showed an increase in basal excitatory synaptic inputs and a decrease in basal inhibitory synaptic inputs compared with neurons from control rats. There was no difference between control and CVS-treated rats in the rapid glucocorticoid suppression of excitatory synaptic inputs, a fast feedback mechanism. In vivo, CVS-treated rats showed an increase in ACTH secretion at baseline and after both iv CRH and acute stress and no impairment of the corticosterone suppression of the ACTH response, compared with controls. In an in vitro pituitary preparation, an increase in basal ACTH release, a small increase in CRH-induced ACTH release, and no decrement in the glucocorticoid suppression of ACTH release were seen in pituitaries from CVS rats. Thus, CVS does not suppress rapid glucocorticoid negative feedback at the hypothalamus or pituitary, but increases the synaptic excitability of paraventricular nucleus CRH neurons and the CRH sensitivity of the pituitary. Therefore, increased HPA activity in chronically stressed male rats is due to sensitization of the HPA axis, rather than to desensitization to rapid glucocorticoid feedback.
authors.affiliation: Department of Cell and Molecular Biology (A.J.F., C.C., T.S., A.A.S., S.D., J.G.T.) and Neuroscience Program (A.Z., J.G.T.), Tulane University, New Orleans, Louisiana 70118; Departments of Physiology and Medicine (A.Z.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and Department of Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Alier J
authors.initials: AJ
authors.lastname: Franco
authors.affiliation: Department of Cell and Molecular Biology (A.J.F., C.C., T.S., A.A.S., S.D., J.G.T.) and Neuroscience Program (A.Z., J.G.T.), Tulane University, New Orleans, Louisiana 70118; Departments of Physiology and Medicine (A.Z.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and Department of Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Cell and Molecular Biology (A.J.F., C.C., T.S., A.A.S., S.D., J.G.T.) and Neuroscience Program (A.Z., J.G.T.), Tulane University, New Orleans, Louisiana 70118; Departments of Physiology and Medicine (A.Z.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and Department of Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Tyler
authors.initials: T
authors.lastname: Scullen
authors.affiliation: Department of Cell and Molecular Biology (A.J.F., C.C., T.S., A.A.S., S.D., J.G.T.) and Neuroscience Program (A.Z., J.G.T.), Tulane University, New Orleans, Louisiana 70118; Departments of Physiology and Medicine (A.Z.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and Department of Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zsombok
authors.affiliation: Department of Cell and Molecular Biology (A.J.F., C.C., T.S., A.A.S., S.D., J.G.T.) and Neuroscience Program (A.Z., J.G.T.), Tulane University, New Orleans, Louisiana 70118; Departments of Physiology and Medicine (A.Z.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and Department of Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Salahudeen
authors.affiliation: Department of Cell and Molecular Biology (A.J.F., C.C., T.S., A.A.S., S.D., J.G.T.) and Neuroscience Program (A.Z., J.G.T.), Tulane University, New Orleans, Louisiana 70118; Departments of Physiology and Medicine (A.Z.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and Department of Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Shi
authors.initials: S
authors.lastname: Di
authors.affiliation: Department of Cell and Molecular Biology (A.J.F., C.C., T.S., A.A.S., S.D., J.G.T.) and Neuroscience Program (A.Z., J.G.T.), Tulane University, New Orleans, Louisiana 70118; Departments of Physiology and Medicine (A.Z.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and Department of Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
authors.affiliation: Department of Cell and Molecular Biology (A.J.F., C.C., T.S., A.A.S., S.D., J.G.T.) and Neuroscience Program (A.Z., J.G.T.), Tulane University, New Orleans, Louisiana 70118; Departments of Physiology and Medicine (A.Z.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and Department of Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Tasker
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone