ABSTRACT
Title
The anandamide transport inhibitor AM404 reduces the rewarding effects of nicotine and nicotine-induced dopamine elevations in the nucleus accumbens shell in rats
Authors
M. Scherma1, P. Fadda1, Z. Justinová2,3, C. Zanettini2, P. Mascia2, A. Makriyannis4, SK. Vadivel4, I. Gamaleddin5, B. Le Foll5 and SR. Goldberg2 and W. Fratta1
1B.B. Brodie Department of Neuroscience, University of Cagliari, Cagliari, Italy;
2Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA;
3MPRC, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA; 4Center for Drug Discovery, Northeastern University, Boston MA, USA;
5Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, Canada
1B.B. Brodie Department of Neuroscience, University of Cagliari, Cagliari, Italy;
2Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA;
3MPRC, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA; 4Center for Drug Discovery, Northeastern University, Boston MA, USA;
5Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, Canada
Abstract
Emerging evidence suggests that rewarding, and other abuse-related effects of nicotine related to tobacco dependence 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 [1]. We recently reported that the FAAH inhibitor cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597) can reverse the abuse-related behavioral and neurochemical effects of nicotine in rats [2].FAAH inhibitors block the degradation (and thereby magnify and prolong the actions) of the endocannabinoid anandamide (AEA), and also the non-cannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). OEA and PEA are endogenous ligands for peroxisome proliferator-activated receptor-alpha (PPAR-α). Since recent evidence indicates that PPAR-α can modulate nicotine reward [3], it is unclear whether AEA plays a role in the effects of URB597 on nicotine reward. A way to selectively increase endogenous levels of AEA without altering OEA or PEA levels is to inhibit AEA uptake into cells by administering the AEA transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404).To clarify AEA’s role in nicotine reward, we investigated the impact of AM404 on conditioned place preference (CPP), reinstatement of extinguished CPP, locomotor suppression and anxiolysis in an open field, and dopamine elevations in the nucleus accumbens shell induced by nicotine in Sprague Dawley rats. AM404 prevented development of nicotine-induced CPP and impeded nicotine-induced reinstatement of CPP. Furthermore, AM404 reduced nicotine-induced increases in dopamine levels in the nucleus accumbens shell, the terminal area of the brain’s mesolimbic reward system. AM404 did not alter the locomotor suppressive or anxiolytic effect of nicotine. These findings suggest that AEA transport inhibition can counteract the addictive effects of nicotine and that AEA transport may serve as a new target for development of medications for treatment of tobacco dependence.
[1] Scherma et al., 2008a: The endocannabinoid system: a new molecular target for the treatment of tobacco addiction. CNS Neurol Disord Drug Targets. 7:468-81.
[2] Scherma et al., 2008b: Inhibition of anandamide hydrolysis by URB597 reverses abuse-related behavioral and neurochemical effects of nicotine in rats. J Pharmacol Exp Ther. 327(2):482-90.
[3] Mascia et al., Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biol Psychiatry. 69(7):633-41.
[1] Scherma et al., 2008a: The endocannabinoid system: a new molecular target for the treatment of tobacco addiction. CNS Neurol Disord Drug Targets. 7:468-81.
[2] Scherma et al., 2008b: Inhibition of anandamide hydrolysis by URB597 reverses abuse-related behavioral and neurochemical effects of nicotine in rats. J Pharmacol Exp Ther. 327(2):482-90.
[3] Mascia et al., Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biol Psychiatry. 69(7):633-41.