Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

Zuzana Justinova, Leigh V Panlilio, Guillermo Moreno-Sanz, Godfrey H Redhi, Alessia Auber, Maria E Secci, Paola Mascia, Tiziano Bandiera, Andrea Armirotti, Rosalia Bertorelli, Svetlana I Chefer, Chanel Barnes, Sevil Yasar, Daniele Piomelli, Steven R Goldberg

Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: 1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and alpha-type peroxisome proliferator-activated (PPAR-α) receptors; 2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; 3) blocked reinstatement of nicotine seeking induced by re-exposure to either nicotine priming or nicotine-associated cues; and 4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither FAAH inhibitor induced dopamine release in the nucleus accumbens shell-consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation, due to their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.Neuropsychopharmacology accepted article preview online, 10 March 2015. doi:10.1038/npp.2015.62.