title: IL-4/10 prevents stress vulnerability following imipramine discontinuation.
abstract: BACKGROUND
  Identifying stress vulnerability after antidepressant discontinuation may be useful in treating relapses in depression. Previous studies have suggested significant effects of the immune system as well as the central nervous system (CNS) on progression and induction of major depression. In the present study, we hypothesized that the factors that are not rescued by a tricyclic antidepressant imipramine may be associated with stress vulnerability and relapses in depression.
  
  
  METHODS
  To address this issue, mice were exposed to 2 h of restraint stress for 21 consecutive days (chronic restraint stress (CRS)) with or without co-treatment of imipramine. These groups were exposed to an electronic foot shock (FS) as additional stress after imipramine washout. Main targets of stress and antidepressants were analyzed in the hippocampus, lymph node, and serum after a series of depression-like behavior analysis.
  
  
  RESULTS
  In this study, we found for the first time that mice exposed to CRS with a tricyclic antidepressant imipramine co-treatment, which did not show depressive-like behaviors, were vulnerable to subsequent stressful stimuli compared to the non-stressed mice after imipramine washout. CRS mice with imipramine co-treatment did not show any difference in BDNF, serotonin receptors, pro-inflammatory cytokines, or kynurenine pathway in the hippocampus compared to the controls. However, peripheral IL-4, IL-10, and alternatively activated microglial phenotypes in the hippocampus were not restored with sustained reduction in CRS mice despite chronic imipramine administration. Supplementing recombinant IL-4 and IL-10 in co-Imi+CRS mice prevented the stress vulnerability on additional stress and restored factors related to alternatively activated microglia (M2) in the hippocampus.
  
  
  CONCLUSIONS
  Thus, our results suggest that the reduced IL-4 and IL-10 levels in serum with hippocampal M2 markers may be involved in the stress vulnerability after imipramine discontinuation, and the restoration and modulation of these factors may be useful to some forms of depression-associated conditions.
authors.affiliation: Department of Pharmacology, School of Medicine, CHA University, CHA BIO COMPLEX, 335 Pangyo, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.
authors.forename: Arum
authors.initials: A
authors.lastname: Han
authors.affiliation: Department of Pharmacology, School of Medicine, CHA University, CHA BIO COMPLEX, 335 Pangyo, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.|Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Haengdang-dong, Seoul, South Korea.
authors.forename: Hyelim
authors.initials: H
authors.lastname: Yeo
authors.affiliation: Department of Pharmacology, School of Medicine, CHA University, CHA BIO COMPLEX, 335 Pangyo, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Haengdang-dong, Seoul, South Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, CHA University, CHA BIO COMPLEX, 335 Pangyo, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Infectious Disease Medical Research Center, College of Medicine, Hallym University, Chuncheon, 200-702, South Korea.
authors.forename: Chang-Won
authors.initials: CW
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, School of Medicine, CHA University, CHA BIO COMPLEX, 335 Pangyo, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea. minsoo100@cha.ac.kr.
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects*; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal; D003863:Depression / Q000523:psychology; D004597:Electroshock; D005106:Exploratory Behavior / Q000187:drug effects; D005518:Food Preferences; D006624:Hippocampus / Q000473:pathology; D007099:Imipramine / Q000009:adverse effects*; D016753:Interleukin-10 / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D011994:Recombinant Proteins / Q000627:therapeutic use; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000188:drug therapy* / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000523:psychology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D011994:Recombinant Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D007099:Imipramine