title: Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance.
abstract: Psychosocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated social defeat (RSD) promoted microglia activation and social avoidance behavior that persisted for 24days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-inducedsocial avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed social avoidance behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of social avoidant behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation.
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH 43210, USA; Facultad de Odontología, Universidad de Costa Rica, San Pedro, San José 11501-2060, Costa Rica. Electronic address: ramirezchan.1@buckeyemail.osu.edu.
authors.forename: Karol
authors.initials: K
authors.lastname: Ramirez
authors.affiliation: Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA. Electronic address: Daniel.Shea@osumc.edu.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Shea
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH 43210, USA; Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA. Electronic address: Daniel.McKim@osumc.edu.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: McKim
authors.affiliation: Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA. Electronic address: Brenda.Reader@osumc.edu.
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Reader
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH 43210, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, OH 43210, USA; Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA. Electronic address: sheridan.1@osu.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Sheridan
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012919:Social Behavior; D013315:Stress, Psychological / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000929:Antidepressive Agents, Tricyclic; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007099:Imipramine
keywords: Imipramine; Microglia; Psychosocial stress; Social avoidance; Social defeat