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.
Bortolato
Marco
M
Department of Pharmacology, University of California, Irvine, California 92697-4260, USA.
Mangieri
Regina A
RA
Fu
Jin
J
Kim
Janet H
JH
Arguello
Oliver
O
Duranti
Andrea
A
Tontini
Andrea
A
Mor
Marco
M
Tarzia
Giorgio
G
Piomelli
Daniele
D
D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001522:Behavior, Animal; D001549:Benzamides / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002219:Carbamates / Q000627:therapeutic use*; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007099:Imipramine / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D015999:Multivariate Analysis; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy* / Q000473:pathology; D013395:Sucrose / Q000378:metabolism; D013997:Time Factors; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000928:Antidepressive Agents; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D007099:Imipramine; D043884:Receptor, Cannabinoid, CB1; D013395:Sucrose; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester