Alcohol and Alcoholism Advance Access originally published online on November 18, 2004
Alcohol and Alcoholism 2005 40(1):15-24; doi:10.1093/alcalc/agh111
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Alcohol & Alcoholism Vol. 40, No. 1 © Medical Council on Alcohol 2005; all rights reserved
SPECIAL ISSUE ARTICLE
ROLE OF THE ENDOCANNABINOID SYSTEM IN THE DEVELOPMENT OF TOLERANCE TO ALCOHOL
1 Division of Analytical Psychopharmacology, New York State Psychiatric Institute, New York, NY, USA 2 Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA and 3 Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
* Author to whom correspondence should be addressed at: Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Tel: +1 845 398 5452/5454; Fax: +1 845 398 5451; E-mail: hungund{at}nki.rfmh.org or basavaraj{at}nki.rfmh.org
(Received 21 July 2004; first review notified 30 July 2004; in revised form 18 September 2004; accepted 1 October 2004)
The present review evaluates the evidence that the endocannabinoid system plays in the development of tolerance to alcohol. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB1 receptor), which was activated by 
9-tetrahydrocannabinol (9-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. Until now, four fatty acid derivatives identified to be arachidonylethanolamide (AEA), 2-arachidonylglycerol (2-AG), 2-arachidonylglycerol ether (noladin ether) and virodhamine have been isolated from both nervous and peripheral tissues. Both AEA and 2-AG have been shown to mimic the pharmacological and behavioural effects of 9-THC. The role of the endocannabinoid system in the development of tolerance to alcohol was not known until recently. Recent studies from our laboratory have implicated for the first time a role for the endocannabinoid system in development of tolerance to alcohol. Chronic alcohol treatment has been shown to down-regulate CB1 receptors and its signal transduction. The observed downregulation of CB1 receptor function results from the persistent stimulation of the receptors by AEA and 2-AG, the synthesis of which has been shown to be increased by chronic alcohol treatment. The enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid alcohol intake, have significantly reduced CB1 receptor function in the brain, consistent with other studies in which the CB1 receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 receptor gene in excessive alcohol drinking behaviour and development of alcoholism. Ongoing investigations may lead to a better understanding of the mechanisms underlying the development of tolerance to alcohol and to develop therapeutic strategies to treat alcoholism.