RT Journal Article
SR Electronic
T1 Inhibition of Anandamide Hydrolysis by Cyclohexyl Carbamic Acid 3′-Carbamoyl-3-yl Ester (URB597) Reverses Abuse-Related Behavioral and Neurochemical Effects of Nicotine in Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 482
OP 490
DO 10.1124/jpet.108.142224
VO 327
IS 2
A1 Maria Scherma
A1 Leigh V. Panlilio
A1 Paola Fadda
A1 Liana Fattore
A1 Islam Gamaleddin
A1 Bernard Le Foll
A1 Zuzana Justinová
A1 Eva Mikics
A1 Jozsef Haller
A1 Julie Medalie
A1 Jessica Stroik
A1 Chanel Barnes
A1 Sevil Yasar
A1 Gianluigi Tanda
A1 Daniele Piomelli
A1 Walter Fratta
A1 Steven R. Goldberg
YR 2008
UL http://jpet.aspetjournals.org/content/327/2/482.abstract
AB Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB1 receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of Δ9-tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically administered CB1 receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB1 receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 (cyclohexyl carbamic acid 3′-carbamoyl-3-yl ester) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence. The American Society for Pharmacology and Experimental Therapeutics