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

Maria Scherma, Leigh V. Panlilio, Paola Fadda, Liana Fattore, Islam Gamaleddin, Bernard Le Foll, Zuzana Justinová, Eva Mikics, Jozsef Haller, Julie Medalie, Jessica Stroik, Chanel Barnes, Sevil Yasar, Gianluigi Tanda, Daniele Piomelli, Walter Fratta, Steven R. Goldberg

Research output: Contribution to journalArticle

Abstract

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 CB 1 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.

Original languageEnglish (US)
Pages (from-to)482-490
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume327
Issue number2
DOIs
StatePublished - Nov 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Scherma, M., Panlilio, L. V., Fadda, P., Fattore, L., Gamaleddin, I., Le Foll, B., Justinová, Z., Mikics, E., Haller, J., Medalie, J., Stroik, J., Barnes, C., Yasar, S., Tanda, G., Piomelli, D., Fratta, W., & Goldberg, S. R. (2008). 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. Journal of Pharmacology and Experimental Therapeutics, 327(2), 482-490. https://doi.org/10.1124/jpet.108.142224