Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates.
BACKGROUND
CB(1) cannabinoid receptors in the brain are known to participate in the regulation of reward-based behaviors. However, the contribution of each of the endocannabinoid transmitters, anandamide and 2-arachidonoylglycerol (2-AG), to these behaviors remains undefined. To address this question, we assessed the effects of URB597, a selective anandamide deactivation inhibitor, as a reinforcer of drug-seeking and drug-taking behavior in squirrel monkeys.


METHODS
We investigated the reinforcing effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 in monkeys trained to intravenously self-administer Delta(9)-tetrahydrocannabinol (THC), anandamide, or cocaine and quantified brain endocannabinoid levels using liquid chromatography/mass spectrometry. We measured brain FAAH activity using an ex vivo enzyme assay.


RESULTS
URB597 (.3 mg/kg, intravenous) blocked FAAH activity and increased anandamide levels throughout the monkey brain. This effect was accompanied by a marked compensatory decrease in 2-AG levels. Monkeys did not self-administer URB597, and the drug did not promote reinstatement of extinguished drug-seeking behavior previously maintained by THC, anandamide, or cocaine. Pretreatment with URB597 did not modify self-administration of THC or cocaine, even though, as expected, it significantly potentiated anandamide self-administration.


CONCLUSIONS
In the monkey brain, the FAAH inhibitor URB597 increases anandamide levels while causing a compensatory down-regulation in 2-AG levels. These effects are accompanied by a striking lack of reinforcing properties, which distinguishes URB597 from direct-acting cannabinoid agonists such as THC. Our results reveal an unexpected functional heterogeneity within the endocannabinoid signaling system and suggest that FAAH inhibitors might be used therapeutically without risk of abuse or triggering of relapse to drug abuse.
Justinova
Zuzana
Z
Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.
Mangieri
Regina A
RA
Bortolato
Marco
M
Chefer
Svetlana I
SI
Mukhin
Alexey G
AG
Clapper
Jason R
JR
King
Alvin R
AR
Redhi
Godfrey H
GH
Yasar
Sevil
S
Piomelli
Daniele
D
Goldberg
Steven R
SR
D000581:Amidohydrolases / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002853:Chromatography, Liquid / Q000379:methods; D003042:Cocaine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage*; D063388:Endocannabinoids; D008297:Male; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012453:Saimiri; D012646:Self Administration / Q000379:methods; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D003042:Cocaine; D013759:Dronabinol; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C078814:anandamide