QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.142224v1 jpet.108.142224v2 327/2/482    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scherma, M. Articles by Goldberg, S. R. Search for Related Content PubMed PubMed Citation Articles by Scherma, M. Articles by Goldberg, S. R.

BEHAVIORAL PHARMACOLOGY

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

Preclinical Pharmacology Section (M.S., L.V.P., Z.J., J.M., J.S., C.B., S.R.G.) of the Behavioral Neuroscience Research Branch and Psychobiology Section (G.T.) of the Medications Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland; B.B. Brodie Department of Neuroscience, University of Cagliari, Cagliari, Italy (M.S., P.F., W.F.); C.N.R. Institute of Neuroscience, Cagliari, Italy (L.F.); Translational Addiction Research Laboratory (I.G., B.L.F.) and Centre for Addiction and Mental Health (B.L.F.), University of Toronto, Toronto, Canada; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland (Z.J.); Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary (E.M., J.H.); Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland (S.Y.); and Department of Pharmacology, University of California, Irvine, California (D.P.)

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 ⁹-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.

Address correspondence to: Dr. Steven R. Goldberg, Preclinical Pharmacology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Biomedical Research Center 05A711, 251 Bayview Blvd., Baltimore, MD 21224. E-mail: sgoldber{at}mail.nih.gov

This article has been cited by other articles:

				M. Melis, G. Pillolla, A. Luchicchi, A. L. Muntoni, S. Yasar, S. R. Goldberg, and M. Pistis Endogenous Fatty Acid Ethanolamides Suppress Nicotine-Induced Activation of Mesolimbic Dopamine Neurons through Nuclear Receptors J. Neurosci., December 17, 2008; 28(51): 13985 - 13994. [Abstract] [Full Text] [PDF]