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

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.138321v1 326/2/483    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 Merritt, L. L. Articles by Damaj, M. I. Search for Related Content PubMed PubMed Citation Articles by Merritt, L. L. Articles by Damaj, M. I.

NEUROPHARMACOLOGY

The Endogenous Cannabinoid System Modulates Nicotine Reward and Dependence

Department of Pharmacology and Toxicology, Medical Campus, Virginia Commonwealth University, Richmond, Virginia

A growing body of evidence suggests that the endogenous cannabinoid system modulates the addictive properties of nicotine, the main component of tobacco that produces rewarding effects. In our study, complementary transgenic and pharmacological approaches were used to test the hypothesis that the endocannabinoid system modulates nicotine reward and dependence. An acute injection of nicotine elicited normal analgesic and hypothermic effects in cannabinoid receptor (CB)₁ knockout (KO) mice and mice treated with the CB₁ antagonist rimonabant. However, disruption of CB₁ receptor signaling blocked nicotine reward, as assessed in the conditioned place preference (CPP) paradigm. In contrast, genetic deletion, or pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for catabolism of the endocannabinoid anandamide, enhanced the expression of nicotine CPP. Although the expression of spontaneous nicotine withdrawal (14 days, 24 mg/kg/day nicotine) was unaffected in CB₁ KO mice, acute administration of rimonabant (3 mg/kg) ameliorated somatic withdrawal signs in wild-type mice. Increasing endogenous levels of anandamide through genetic or pharmacological approaches exacerbated the physical somatic signs of spontaneous nicotine withdrawal in a milder withdrawal model (7 days, 24 mg/kg/day nicotine). Moreover, FAAH-compromised mice displayed increased conditioned place aversion in a mecamylamine-precipitated model of nicotine withdrawal. These findings indicate that endocannabinoids play a role in the rewarding properties of nicotine as well as nicotine dependence liability. Specifically, increasing endogenous cannabinoid levels magnifies, although disrupting CB₁ receptor signaling, attenuates nicotine reward and withdrawal. Taken together, these results support the hypothesis that cannabinoid receptor antagonists may offer therapeutic advantages to treat tobacco dependence.

Address correspondence to: Dr. M. Imad Damaj, Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613. E-mail: mdamaj{at}vcu.edu

This article has been cited by other articles:

				M. Scherma, L. V. Panlilio, P. Fadda, L. Fattore, I. Gamaleddin, B. Le Foll, Z. Justinova, E. Mikics, J. Haller, J. Medalie, et al. 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 J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 482 - 490. [Abstract] [Full Text] [PDF]