title: IL-1 receptor-antagonist (IL-1Ra) knockout mice show anxiety-like behavior by aging.
abstract: Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus.
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; Division of Cell Biology, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. Electronic address: wakab@ncnp.go.jp.
authors.forename: Chisato
authors.initials: C
authors.lastname: Wakabayashi
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Numakawa
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Odaka
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ooshima
authors.affiliation: Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kiyama
authors.affiliation: Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Manabe
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
authors.affiliation: Division of Cell Biology, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
mesh_terms: D000375:Aging / Q000378:metabolism / Q000523:psychology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000523:psychology*; D015306:Biogenic Monoamines / Q000378:metabolism; D003975:Diazepam / Q000627:therapeutic use; D006624:Hippocampus / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D018782:Maze Learning; D018345:Mice, Knockout; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D015306:Biogenic Monoamines; D053590:Interleukin 1 Receptor Antagonist Protein; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D003975:Diazepam
keywords: Anxiety-like phenotype; Elevated plus-maze test; Glucocorticoid receptor; Hippocampus; IL-1 receptor antagonist