Antidepressant-like Activity of the Fatty Acid Amide Hydrolase Inhibitor URB597 in a Rat Model of Chronic Mild Stress

Abstract

Background:The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents.

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

“…Notably, in our experiments, neither URB597, JZL184, nor combo treatment reversed the depression-like behavior observed in CUS mice. Although the anti-depressant properties of URB597 (Bortolato et al, 2007) and JZL184 (Zhong et al, 2014) in stress-exposed rodents have been reported, several factors (animal species, type of behavioral test, duration and type of stressors, design of treatment, dose of drugs) may explain the Endocannabinoid system modulation of stress-induced pain E Lomazzo et al discrepancy between our data and previous studies. Further investigations should shed light on these differences in efficacy of treatments.…”

“…Consistent with previous reports (Bortolato et al, 2007), CUS did not affect the basal level of AEA (Figure 4), 2-AG ( Figure 5), and PEA (Supplementary Figure 2) in any of the tissues examined. Nevertheless, in the serum of vehicle-treated CUS mice a decrease in AEA (Figure 4g) and PEA (Supplementary Figure 2g) was observed as compared with controls, although it was not statistically significant (p ¼ 0.2).…”

“…Interestingly, in the GS muscle, the basal levels of AEA (Figure 4h), 2-AG (Figure 5h), and PEA (Supplementary Figure 2h) were about 5-to 10-fold lower compared with the brain. URB597 treatment increased AEA level by about a twofold in most brain regions (Figure 4a-d) and in GS muscle (Figure 4h) of both control and CUS mice but was not significant in hippocampus and less pronounced in prefrontal cortex, as reported before (Bortolato et al, 2007). In midbrain (Figure 4e) and spinal cord (Figure 4f), URB597 increased AEA level by about a sixfold, indicating that pharmacological inhibition of FAAH increases AEA level to different extents in tissues.…”

“…On the other hand, exposure to chronic heterotypic stress (CUS) produces more variable results (ie, no change in eCB levels), likely due to triggering of adaptive mechanisms (Hill and Patel, 2013). Indeed, consistent with Bortolato et al (2007), we found no substantial alterations in eCB contents in brain and GS muscle of CUS mice versus controls. Although we did not detect an 'AEA-deficient state' in CUS mice, URB597 exerted anxiolytic and analgesic effects (discussed later), suggesting that in mice exposed to chronic heterotypic stress (CUS) enhancement of the 'AEA state' is beneficial.…”

“…The reduced increase of AEA levels by URB597 in brain regions involved in the modulation of emotional states (hippocampus and prefrontal cortex) is surprising. However, prolonged exposure to the drug has been proposed to lead to a 'downregulation of AEA mobilization' in certain brain tissues (ie, hippocampus) by mechanisms that remain yet largely unknown (Bortolato et al, 2007). Interestingly, in CUS mice, URB597 induced a statistically significant increase in AEA and PEA serum levels ( Figure 4g and Supplementary Figure 2g) as compared with vehicle-treated CUS animals, indicating that the drug was able to reverse the apparent basal decrease of AEA and PEA observed in CUS mice as compared with controls.…”