Background: Depression has been associated with a low-grade inflammation and immune activation, as revealed by clinical studies showing elevated levels of pro-inflammatory cytokines and acute phase proteins in depressed patients. These patients are often treatment-resistant, and some studies show that elevated markers of inflammation predict a poor response to treatment. Furthermore, increasing evidences show that metabolic abnormalities such as obesity and diabetes mellitus type 2 are associated with a low-grade inflammation. Objectives: The aim of this study is to investigate the effects of a systemic low-grade inflammation induced by lipopolysaccharide (LPS) on adult Sprague-Dawley rats on depression-like and metabolic parameters. Methods: Chronic infusion of LPS (at a high, medium and low dose) for 28 days was performed by using subcutaneously implanted osmotic minipumps (Alzet(registered trademark) 2ML4, infusion rate 2.5l/day), which delivers LPS through a catheter into the abdomen. Depression-like behavior was assessed as increased time spent immobile in the forced swim test (FST). Peripheral markers of a low-grade inflammation was measured using a high sensitivity ELISA kit and central levels of pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6) together with the expression of enzymes involved in the tryptophan-kynurenine pathway, will be analyzed in specific brain regions using real-time qPCR. Body weight and food intake was measured once a week, while fasting glucose and insulin sensitivity was assessed after four weeks of LPS administration. Findings and conclusion: Our results showed that a low dose of LPS increased immobility in the FST relative to vehicle treatment, indicative of depression-like behavior. We did not find any difference in body weight, fasting glucose and insulin values. However, a high dose of LPS caused an increase in liver weight. Analysis of cytokine and mRNA expression levels is currently being carried out and these results are pending. Our preliminary results indicate that a low dose of LPS can produce depression-like behavior, without inducing metabolic disturbances or sickness behavior. Thus, this model might help elucidating some of the mechanisms underlying inflammation-associated depression, in order to assist in developing more effective treatment strategies for this group of patients.
Acta Neuropsychiatrica, 2012, Vol 24
lipopolysaccharide cytokine glucose marker tumor necrosis factor alpha kynurenine tryptophan acute phase protein enzyme interleukin 6 insulin interleukin 1 messenger RNA inflammation model college psychopharmacology metabolic parameters human low drug dose patient non insulin dependent diabetes mellitus diet restriction body weight forced swim test insulin sensitivity food intake abdomen catheter obesity infusion rate infusion brain region clinical study Sprague Dawley rat liver weight immobilization drug megadose metabolic disorder illness behavior adult enzyme linked immunosorbent assay