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

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. Methods: We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression. Results: Daily administration of URB597 (.3 mg·kg-1, intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg·kg-1, once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg·kg-1) or ineffective (.03 mg·kg-1). Treatment with URB597 (.3 mg·kg-1) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus. Conclusions: URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain