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 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.
Footnotes
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This study was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; by the Italian Ministry of University and Scientific Research and the Centre of Excellence on “Neurobiology of Dependence”; the Department of Psychiatry, University of Maryland School of Medicine; the Institute of Experimental Medicine, Hungarian Academy of Sciences; the Centre for Addiction and Mental Health and University of Toronto; the Division of Geriatric Medicine and Gerontology of Johns Hopkins University School of Medicine; and the Department of Pharmacology, University of California, Irvine. The reinstatement of conditioned place preference experiments was supported, in part, by a grant from Philip Morris USA and Philip Morris International.
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Parts of this work were previously presented at the following conference: Scherma M, Panlilio LV, Fadda P, Fattore L, Gamaleddin I, Le Foll B, Justinová Z, Mikics E, Haller J, Medalie J, et al. (2007) Inhibition of anandamide hydrolysis by URB597 (cyclohexyl carbamic acid 3′-carbamoyl-3-yl ester) reverses abuse-related behavioral and neurochemical effects of nicotine in rats. 37th Annual Meeting of the Society for Neuroscience; 2007 Nov 3–7; San Diego, CA. Program no. 843.7, Society for Neuroscience, Washington, DC.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.142224.
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ABBREVIATIONS: CPP, conditioned place preference; VTA, ventral tegmental area; AEA, anandamide; FAAH, fatty acid amide hydrolas; URB597, cyclohexyl carbamic acid 3′-carbamoyl-3-yl ester; FR, fixed ratio; WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone; ANOVA, analysis of variance; OEA, oleoylethanolamide; PEA, palmitoylethanolamide; PPAR, peroxisome proliferator-activated nuclear receptor.
- Received June 12, 2008.
- Accepted August 13, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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