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J Psychiatr Res. 2018 Dec;107:57-67. doi: 10.1016/j.jpsychires.2018.10.003. Epub 2018 Oct 5.

Major depression model induced by repeated and intermittent lipopolysaccharide administration: Long-lasting behavioral, neuroimmune and neuroprogressive alterations.

Author information

1
Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil. Electronic address: taciana7maia@gmail.com.
2
Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil. Electronic address: romariomattos@gmail.com.
3
Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil. Electronic address: camilacarvalhoenf@yahoo.com.br.
4
Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil. Electronic address: elicleciors@gmail.com.
5
Department of Morphology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil. Electronic address: deiziane2009@gmail.com.
6
Universidade Federal do Semiárido, Centro de Engenharias, Departamento de Engenharia e Tecnologia, Mossoró, RN, Brazil. Electronic address: claudio.costa@ufersa.edu.br.
7
Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; Fundação Oswaldo Cruz - FIOCRUZ-CE, Fortaleza, Ceará, Brazil. Electronic address: fabiom@ufc.br.
8
Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
9
Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil. Electronic address: silvania_vasconcelos@yahoo.com.br.
10
Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX, 77054, USA; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina-UNESC, Criciúma, SC, Brazil; Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address: tatiana.Barichello@uth.tmc.edu.
11
Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX, 77054, USA; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina-UNESC, Criciúma, SC, Brazil; Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address: Joao.L.DeQuevedo@uth.tmc.edu.
12
Impact Strategic Research Center, Deakin University, Geelong, Australia; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Electronic address: dr.michaelmaes@hotmail.com.
13
Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil. Electronic address: daviddelucena@me.com.
14
Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; National Institute for Translational Medicine (INCT-TM, CNPq), Ribeirão Preto, Brazil. Electronic address: daniellesilmacedo@gmail.com.

Abstract

Major depressed patients show increased bacterial translocation with elevated plasma levels of lipopolysaccharide (LPS), which may trigger immune-inflammatory and neuro-oxidative responses. Recently, an animal model based on chronic LPS administration was developed which was associated with long-lasting depressive-like and neuro-oxidative alterations in female mice. The aim of the current study was to investigate behavioral, neuroimmune and neuroprogressive alterations in female mice 6 weeks after LPS chronic exposure. Female mice received increasing doses of LPS during 5 days at one-month intervals repeated for 4 consecutive months. Six weeks after the last LPS-exposure, we assessed behavioral despair and anhedonia, microglial activation, alterations in tryptophan, 5-HT, kynurenine, quinolinic acid (QUIN) levels and spermidine/spermine N1-acetyltransferase (SAT1) expression in the hippocampus, both with and without fluoxetine administration. Our results show that six weeks post-LPS, mice present behavioral despair and anhedonia in association with increased IBA1 expression (a microglia activation marker), NF-kB p65 and IL-1β levels, indoleamine 2,3-dioxygenase (IDO1) mRNA expression, kynurenine, QUIN levels and QUIN/tryptophan ratio, and lowered tryptophan, 5-HT levels and SAT1 mRNA expression. Fluoxetine reversed the behavioral and neuroimmune alterations but had no effect in the reversal of IDO1 increased expression, QUIN levels and QUIN/tryptophan ratio. In conclusion, our results support the validity of the chronic LPS model of major depression and additionally shows its translational relevance with respect to neuroimmune and neuroprogressive pathways.

KEYWORDS:

Chronic depression; Forced swimming test; LPS; Neuroinflammation; SAT1; Tryptophan catabolism

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