Comorbid anxiety-like behavior in a rat model of colitis is mediated by an upregulation of corticolimbic fatty acid amide hydrolase

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.

Vasopressin and central control of the cardiovascular system: A 40‐year retrospective

“…Furthermore, these inflammatory conditions, as well as stress, have also been shown to be associated with alterations in cannabinoid signalling in other brain areas. 75,76 Given the pivotal role of endocannabinoids in PVN function, 77 alterations in signalling to pre-autonomic AVP neurones during peripheral inflammation could be explored.…”

Genetic Variants of Fatty Acid Amide Hydrolase Modulate Acute Inflammatory Responses to Colitis in Adult Male Mice

“…Furthermore, elevated indices of amygdala activation are also observed in patients with gastrointestinal diseases, including, irritable bowel syndrome, and IBD ( Naliboff and Mayer, 2006 ; Labus et al, 2009 , 2013 ; Agostini et al, 2011 ; Fukudo and Kanazawa, 2011 ; Hubbard et al, 2011 ; Tillisch et al, 2011 ; Bao et al, 2015 ; Icenhour et al, 2015 ; Weaver et al, 2016 ; Fan et al, 2019 ). We previously showed in a rodent colitis model that the amygdalar eCB system is altered, and that these changes contribute to anxiety-like behavior in rats ( Vecchiarelli et al, 2021 ). Given that FAAH inhibition ameliorates colitis-induced anxiety, and has the ability to suppress inflammatory processes, it remains possible that one mechanism by which elevated AEA signaling in the amygdala could reduce inflammation-associated anxiety is via the suppression of inflammatory cytokines.…”

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“…Furthermore, elevated indices of amygdala activation are also observed in patients with gastrointestinal diseases, including, irritable bowel syndrome, and IBD (Naliboff and Mayer, 2006;Labus et al, 2009Labus et al, , 2013Agostini et al, 2011;Fukudo and Kanazawa, 2011;Hubbard et al, 2011;Tillisch et al, 2011;Bao et al, 2015;Icenhour et al, 2015;Weaver et al, 2016;Fan et al, 2019). We previously showed in a rodent colitis model that the amygdalar eCB system is altered, and that these changes contribute to anxiety-like behavior in rats (Vecchiarelli et al, 2021). Given that FAAH inhibition ameliorates colitis-induced anxiety, and has the ability to suppress inflammatory processes, it remains possible that one mechanism by which elevated AEA signaling in the amygdala could reduce inflammation-associated anxiety is via the suppression of inflammatory cytokines.…”

“…Following macroscopic tissue damage assessment, a sample of colon was excised, snap frozen, and stored at −80 • C for later use in a myeloperoxidase (MPO) activity assay, as previously described (Sigalet et al, 2010;Vecchiarelli et al, 2021). Briefly, samples were homogenized in hexadecyltrimethylammonium bromide (HTAB; Sigma-Aldrich, Darmstadt, Germany, #H5882) in potassium phosphate buffer, homogenized using a 5 mm stainless-steel bead (Qiagen, Hilden, Germany, #69989) and TissueLyser LT bead homogenizer (Qiagen) for 10 min at 5 Hz and centrifuged for 10 min at 15871 × g at 4 • C. Supernatant was added to hydrogen peroxide and o-dianisidine dihydrochloride in a 96 well-plate.…”

“…As previously described (Vecchiarelli et al, 2016), plasma was separated from trunk blood following collection by centrifugation for 20 min at 10,000 × g at 4 • C. Plasma was aliquoted and stored at −80 • C. Amygdalae were micro-dissected (Gray et al, 2015;Vecchiarelli et al, 2016Vecchiarelli et al, , 2021) and stored at −80 • C prior to processing for cytokine ELISAs. Samples were placed in 10 µL/mg of homogenization buffer [150 mM sodium chloride, 2.5 mm magnesium chloride, 5 mg/500 mL aprotinin and cOmplete TM protease inhibitors (Millipore Sigma, #11836145001)].…”