Colitis promotes anxiety through a corticotropin-releasing factor receptor 1 mediated suppression of central anandamide signaling

There is a large degree of comorbidities between inflammatory diseases and stress-associated neuropsychiatric disorders. However, the mechanisms underlying these comorbidities have not been fully elucidated. Endocannabinoids regulate anxiety and inflammation, making them a potential candidate to investigate the mechanism of these comorbidities. We employed an animal model of colitis (intracolonic trinitrobenzene sulfonic acid) to explore the role of endocannabinoids in this process in adult male rats. We previously showed that levels of anandamide (AEA) were decreased in the amygdala, hippocampus and medial prefrontal cortex, at one week after the induction of colitis. Furthermore, colitis was associated with an increase in fatty acid amide hydrolase (FAAH) activity in these regions, indicating that peripheral inflammation increases central AEA hydrolysis. We also saw an increase in anxiety like-behaviour in the elevated plus maze. We now show that this increase in anxiety can be reversed with an acute intracerebroventricular administration a FAAH inhibitor, which increases AEA levels. Additionally, central administration of an antagonist of the corticotropin releasing factor receptor 1 (CRF-R1) during colitis reversed the AEA reductions in the amygdala and hippocampus, indicating that the AEA reductions relevant for the generation of anxiety during colitis are regulated through a CRF-R1-driven increase in FAAH activity. Together these findings add to the understanding of central mechanisms underlying anxiety-like behaviours associated with peripheral inflammation.