Abstract
Peripheral inflammatory conditions, including those localized to the gastrointestinal tract, are highly comorbid with psychiatric disorders such as anxiety and depression. These behavioral symptoms are poorly managed by conventional treatments for inflammatory diseases and contribute to quality of life impairments. Peripheral inflammation is associated with sustained elevations in circulating glucocorticoid hormones, which can modulate central processes, including those involved in the regulation of emotional behavior. The endocannabinoid (eCB) system is exquisitely sensitive to these hormonal changes and is a significant regulator of emotional behavior. The impact of peripheral inflammation on central eCB function, and whether this is related to the development of these behavioral comorbidities remains to be determined. To examine this, we employed the trinitrobenzene sulfonic acid-induced model of colonic inflammation (colitis) in adult, male, Sprague Dawley rats to produce sustained peripheral inflammation. Colitis produced increases in behavioral measures of anxiety and elevations in circulating corticosterone. These alterations were accompanied by elevated hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which hydrolyzes the eCB anandamide (AEA), throughout multiple corticolimbic brain regions. This elevation of FAAH activity was associated with broad reductions in the content of AEA, whose decline was driven by central corticotropin releasing factor type 1 receptor signaling. Colitis-induced anxiety was reversed following acute central inhibition of FAAH, suggesting that the reductions in AEA produced by colitis contributed to the generation of anxiety. These data provide a novel perspective for the pharmacological management of psychiatric comorbidities of chronic inflammatory conditions through modulation of eCB signaling.
Highlights
In peripheral inflammatory conditions, such as inflammatory bowel diseases (IBD), comorbid anxiety and depression are associated with increased disease activity, greater rate of relapse and reduced responsiveness to therapies [1,2,3,4,5], significantly reducing patient quality of life [6, 7]
Pharmacological intervention - biochemical studies To understand the role of corticotropin-releasing factor (CRF) signaling on the colitis-induced reductions of AEA signaling, we examined the impact of sustained disruption of CRF-R1 signaling during the entire duration of colitis (i.e., 7 days) utilizing continuous drug infusion with an osmotic mini-pump (Alzet, Cupertino, CA, USA; Model 2002; 0.5 μL/h) connected to a 5 mm cannula (Alzet, Brain Infuser Kit 2) [101]
Colitis induction produced behavioral indices of increased anxietylike behavior Data presented on colitis phenotype are a representative set of data from the rats used for AEA and 2-AG analysis, but these effects were consistent across all experimental cohorts
Summary
In peripheral inflammatory conditions, such as inflammatory bowel diseases (IBD), comorbid anxiety and depression are associated with increased disease activity, greater rate of relapse and reduced responsiveness to therapies [1,2,3,4,5], significantly reducing patient quality of life [6, 7]. It is likely that the driving force behind these psychiatric comorbidities is disease activity [8, 13, 30,31,32,33,34,35], implying, at least partially, that inflammation and a dysregulation of the gut-brain axis may be involved in the pathogenesis of psychiatric comorbidities in IBD Both basally and during disease states, the gut-brain axis allows for bidirectional communication between the brain and the gut, including at the levels of the autonomic nervous system and circumventricular organs [36]. One system known to be sensitive to hormonal components of the HPA axis, and that is a significant regulator of emotional behavior, is the endocannabinoid (eCB) system [41,42,43]
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