Behavioral despair associated with a mouse model of Crohn's disease: Role of nitric oxide pathway

Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:131-41. doi: 10.1016/j.pnpbp.2015.08.004. Epub 2015 Aug 9.

Abstract

Crohn's disease (CD) is associated with increased psychiatric co-morbidities. Nitric oxide (NO) is implicated in inflammation and tissue injury in CD, and it may also play a central role in pathogenesis of the accompanying behavioral despair. This study investigated the role of the NO pathway in behavioral despair associated with a mouse model of CD. Colitis was induced by intrarectal (i.r.) injection of 2,4,6-trinitrobenzenesulfonic acid (10mg TNBS in 50% ethanol). Forced swimming test (FST), pharmacological studies and tissues collection were performed 72 h following TNBS administration. To address a possible inflammatory origin for the behavioral despair following colitis induction, tumor necrosis factor-alpha (TNF-α) level was measured in both the hippocampal and colonic tissue samples. In parallel, hippocampal inducible nitric oxide synthase (iNOS) and nitrite level were evaluated. Pharmacological studies targeting the NO pathway were performed 30-60 min before behavioral test. Colitis was confirmed by increased colonic TNF-α level and microscopic score. Colitic mice demonstrated a significantly higher immobility time in the FST associated to a significant increase of hippocampal TNF-α, iNOS expression and nitrite content. Acute NOS inhibition using either Nω-nitro-l-arginine methyl ester (a non-specific NOS inhibitor) or aminoguanidine hydrochloride (a specific iNOS inhibitor) decreased the immobility time in colitic groups. Moreover, acute treatment with both NOS inhibitors decreased the TNF-α level and nitrite content in the hippocampal samples. This study suggests that the NO pathway may be involved in the behavioral effects in the mouse TNBS model of CD. These findings endow new insights into the gut-brain communication during the development of colonic inflammation, which may ultimately lead to improved therapeutic strategies to combat behavior changes associated with gastrointestinal disorders.

Keywords: Behavioral despair; Inflammatory bowel disease; Nitric oxide; TNF-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Colitis / pathology
  • Colitis / physiopathology
  • Colitis / psychology
  • Colon / drug effects
  • Colon / metabolism
  • Colon / pathology
  • Crohn Disease / drug therapy
  • Crohn Disease / pathology
  • Crohn Disease / physiopathology*
  • Crohn Disease / psychology*
  • Depression / drug therapy
  • Depression / pathology
  • Depression / physiopathology*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Guanidines / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Male
  • Mice
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / metabolism*
  • Nitrites / metabolism
  • Signal Transduction / drug effects
  • Trinitrobenzenesulfonic Acid
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antidepressive Agents
  • Enzyme Inhibitors
  • Guanidines
  • Nitrites
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Trinitrobenzenesulfonic Acid
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • pimagedine
  • NG-Nitroarginine Methyl Ester