title: Mineralocorticoid receptor antagonist spironolactone prevents chronic corticosterone induced depression-like behavior.
abstract: High level of serum corticosteroid is frequently associated with depression, in which a notable HPA (hypothalamus-pituitary-adrenal) axis hyperactivity is often observed. There are two types of corticosteroid receptors expressed in the hippocampus that provide potent negative feedback regulation on the HPA axis but dysfunction during depression, i.e. the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The balance between hippocampal MR and GR during chronic stress plays an important role in the occurrence of depression. The aim of this study is to explore if chronic corticosterone administration would induce depression-like behavior and affect the expression and function of hippocampal MR and GR, in addition to assess whether manipulation of corticosteroid receptors would modulate depressive behaviors. Hence, mice were treated with corticosterone (40 mg/kg) for 21 days followed by assessment in a battery of depression-like behaviors. The results show that chronic corticosterone-treated animals displayed an increased immobility time in a forced-swimming test, decreased preference to sucrose solution and novel object recognition performance, and enhanced hippocampal serotonin but decreased MR expression in both hippocampus and hypothalamus. On the other hand, co-administration of MR antagonist, spironolactone (25mg/kg, i.p. × 7 days) in corticosteroid-treated animals reduced immobility time in a forced-swimming test and improved performance in a novel object recognition test. In conclusion, we demonstrate that chronic corticosterone treatment triggers several depression-like behaviors, and in parallel, down-regulates MR expression in the hippocampus and hypothalamus. Administration of an MR antagonist confers an anti-depressant effect in chronic corticosterone-treated animals.
authors.affiliation: Department of Physiology and Pharmacology, Graduate Institute of Biomedical Sciences, Chang-Gung University, 259 Wen-Hwa 1st Road, Tao-Yuan 333, Taiwan.
authors.forename: Ting-Ching
authors.initials: TC
authors.lastname: Wu
authors.forename: Han-Ting
authors.initials: HT
authors.lastname: Chen
authors.forename: Han-Ying
authors.initials: HY
authors.lastname: Chang
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Yang
authors.forename: Mei-Chun
authors.initials: MC
authors.lastname: Hsiao
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Cheng
authors.forename: Jin-Chung
authors.initials: JC
authors.lastname: Chen
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003345:Corticosterone / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000097:blood; D003863:Depression / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013148:Spironolactone / Q000627:therapeutic use*; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D050486:Serotonin Plasma Membrane Transport Proteins; D013148:Spironolactone; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014365:Tryptophan Hydroxylase; D003345:Corticosterone