Abstract
AimsA disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them.MethodsFunctional dyspepsia was induced by neonatal gastric irritation in male rats. 10-day old male Sprague-Dawley rats received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days. At 8–10 weeks of age, rats were tested with sucrose preference and forced-swimming tests to examine depression-like behavior. Elevated plus maze, open field and light-dark box tests were used to test anxiety-like behaviors. ACTH and corticosterone responses to a minor stressor, saline injection, and hypothalamic CRF expression were also measured.ResultsBehavioral tests revealed changes of anxiety- and depression-like behaviors in IA-treated, but not control rats. As compared with controls, hypothalamic and amygdaloid CRF immunoreactivity, basal levels of plasma corticosterone and stress-induced ACTH were significantly higher in IA-treated rats. Gastric sensory ablation with resiniferatoxin had no effect on behaviors but treatment with CRF type 1 receptor antagonist, antalarmin, reversed the depression-like behavior in IA-treated ratsConclusionsThe present results suggest that transient gastric irritation in the neonatal period can induce a long lasting increase in depression- and anxiety-like behaviors, increased expression of CRF in the hypothalamus, and an increased sensitivity of HPA axis to stress. The depression-like behavior may be mediated by the CRF1 receptor. These findings have significant implications for the pathogenesis of psychological co-morbidity in patients with functional bowel disorders.
Highlights
Functional dyspepsia (FD), defined as persistent or recurrent pain in the upper abdomen presumably of gastroduodenal origin but without any structural etiology to explain the symptoms, is a common clinical gastrointestinal disorder that affects 15–20% of the population [1,2,3,4]
Our results suggest that transient gastric irritation in the neonatal period can induce long-lasting increases in depression,and anxiety-like behaviors and increase in the Hypothalamic Pituitary Axis (HPA) axis sensitivity to stress that is associated with increase the expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN) of the hypothalamus
The percentage of rats with sucrose consumption of $75% was significantly reduced in IA-treated rats (45%) relative to the control rats (80%, P,0.05 by Chi-square test, n = 20 per group; Figure 1A)
Summary
Functional dyspepsia (FD), defined as persistent or recurrent pain in the upper abdomen presumably of gastroduodenal origin but without any structural etiology to explain the symptoms, is a common clinical gastrointestinal disorder that affects 15–20% of the population [1,2,3,4]. A major theme in this field is that psychological/ psychiatric problems have a pathogenic role, based both on the observation that patients with FD are more anxious and depressed than healthy controls[1,3,4,5], as well as research linking stress and depression to altered gastrointestinal sensory and motor function [6,7,8,9,10]. We hypothesized that primary visceral disturbances in early life can result in persistent behavioral and emotional abnormalities. This hypothesis is based on our previous published work showing that the neonatal period is a vulnerable period for the viscera. Transient inflammation or injury of either the stomach or colon result in long-lasting hypersensitivity and motor abnormalities that persist despite complete resolution of the initial insult [11,12,13,14]
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