Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are incurable lifelong inflammatory bowel diseases (IBD) with a rising worldwide incidence. IBD is characterized by diarrhea, rectal bleeding, severe cramping and weight loss. However, there is a growing evidence that IBD is also associated with anxiety- and depression-related disorders, which further increase the societal burden of these diseases. Given the limited knowledge of central nervous system (CNS) changes in IBD, we investigated CNS-related comorbidities in a mouse model of experimental colitis induced by dextran sulfate sodium (DSS) administration in drinking water for 5 days. In male and female C57BL6J mice, DSS treatment caused increased brain excitability, revealed by a decrease in seizure onset times after intraperitoneal administration of kainic acid. Moreover, both sexes showed increased anxiety-related behavior in the elevated plus-maze (EPM) and open field (OF) paradigms. We assessed somatic pain levels, because they may influence behavioral responses. Only male mice were hyperalgesic when tested with calibrated von Frey hairs and on the hotplate for mechanical and thermal pain sensitivity respectively. Administration of diazepam (DZP; ip, 1 mg/kg) 30 min before EPM rescued the anxious phenotype and improved locomotion, even though it significantly increased thermal sensitivity in both sexes. This indicates that the altered behavioral response is unlikely attributable to an interference with movement due to somatic pain in females. We show that experimental colitis increases CNS excitability in response to administration of kainic acid, and increases anxiety-related behavior as revealed using the EPM and OF tests.
Highlights
Ulcerative colitis (UC) and Crohn’s disease (CD) are a group of chronic idiopathic inflammatory bowel diseases (IBD) that are characterized by inflammation of the gastrointestinal (GI) tract and severe symptoms including diarrhea, rectal bleeding, severe cramping and weight loss
We show that experimental colitis increases central nervous system (CNS) excitability in response to administration of KA, and increases anxiety-related behavior as revealed on the elevated plus-maze (EPM) and open field (OF)
We found increased mechanical and thermal pain sensitivity in males but not in females, and DZP significantly increased the thermal pain sensitivity after dextran sulfate sodium (DSS) in both males and females
Summary
Ulcerative colitis (UC) and Crohn’s disease (CD) are a group of chronic idiopathic inflammatory bowel diseases (IBD) that are characterized by inflammation of the gastrointestinal (GI) tract and severe symptoms including diarrhea, rectal bleeding, severe cramping and weight loss. The prevalence of anxiety and depression are not necessarily related to disease activity (Mikocka-Walus et al, 2016). These psychiatric comorbidities can significantly reduce the quality of life of patients, and contribute significantly to the indirect costs of IBD (Vidal et al, 2008). Studies using an animal model of IBD induced by dextran sulfate sodium (DSS) administration have demonstrated cognitive impairment, anxiety-like and depressive-like behavior, and decreased social interactions (Bercik et al, 2011; Painsipp et al, 2011; Jain et al, 2015; Emge et al, 2016). A recent study of patients with IBD suggested that women with active disease reported increased anxiety, depression and reduced quality of life (Tribbick et al, 2017). One study has reported that in the acute DSS model only male mice show an anxious phenotype on the elevated plus-maze (EPM), whereas females show a more depressive-like phenotype in the forced swim test (Painsipp et al, 2011)
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