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The Journal of Neuroscience, April 4, 2007, 27(14):3695-3702; doi:10.1523/JNEUROSCI.4403-06.2007

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Behavioral/Systems/Cognitive
Specific Alterations of Extracellular Endocannabinoid Levels in the Nucleus Accumbens by Ethanol, Heroin, and Cocaine Self-Administration

Stéphanie Caillé,² Lily Alvarez-Jaimes,¹ Ilham Polis,¹ David G. Stouffer,¹ and Loren H. Parsons¹

¹Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and ²Laboratoire Neuropsychobiologie des Desadaptations, Université Victor Ségalen Bordeaux 2, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, 33076 Bordeaux Cedex, France

Correspondence should be addressed to Loren H. Parsons, Committee on the Neurobiology of Addictive Disorders, SP30-2120, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Email: lparsons{at}scripps.edu

Ethanol and opiate self-administration are sensitive to manipulations of cannabinoid CB₁ receptor function and, from this, a role for the endogenous cannabinoid system in the modulation of drug reward has been hypothesized. However, direct in vivo evidence of drug-induced alterations in brain endocannabinoid (eCB) formation has been lacking. To address this issue, we explored the effect of drug self-administration on interstitial eCB levels in the nucleus accumbens (NAc) shell using in vivo microdialysis. Ethanol, heroin, and cocaine were compared because the rewarding properties of ethanol and heroin are reduced by CB₁ receptor inactivation, whereas cocaine reward is less sensitive to these manipulations. Ethanol self-administration significantly increased dialysate 2-arachidonoylglycerol (2-AG) levels with no concomitant change in dialysate anandamide (AEA) concentrations. Conversely, heroin self-administration significantly increased dialysate AEA levels, and induced a subtle but significant decrease in dialysate 2-AG levels. In each case, the relative change in dialysate eCB content was significantly correlated with the amount of drug consumed. In contrast, cocaine self-administration did not alter dialysate levels of either AEA or 2-AG. Local infusion of the CB₁ antagonist SR 141716A into the NAc significantly reduced ethanol, but not cocaine, self-administration. Together with our previous observation that intra-NAc SR 141716A reduces heroin self-administration, these data provide novel in vivo support for an eCB involvement in the motivational properties of ethanol and heroin but not cocaine. Furthermore, the selective effects of ethanol and heroin on interstitial 2-AG and AEA provide new insight into the distinct neurochemical profiles produced by these two abused substances.

Key words: anandamide; 2-AG; SR 141716A; CB₁ receptor; microdialysis; addiction

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Received Oct. 10, 2006; revised March 6, 2007; accepted March 6, 2007.

Correspondence should be addressed to Loren H. Parsons, Committee on the Neurobiology of Addictive Disorders, SP30-2120, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Email: lparsons{at}scripps.edu

This article has been cited by other articles:

				L. Orio, S. Edwards, O. George, L. H. Parsons, and G. F. Koob A Role for the Endocannabinoid System in the Increased Motivation for Cocaine in Extended-Access Conditions J. Neurosci., April 15, 2009; 29(15): 4846 - 4857. [Abstract] [Full Text] [PDF]

				R. Spanagel Alcoholism: A Systems Approach From Molecular Physiology to Addictive Behavior Physiol Rev, April 1, 2009; 89(2): 649 - 705. [Abstract] [Full Text] [PDF]

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