title: Neuromodulatory role of the endocannabinoid signaling system in alcoholism: an overview.
abstract: The current review evaluates the evidence that some of the pharmacological and behavioral effects of ethanol (EtOH), including EtOH-preferring behavior, may be mediated through the endocannabinoid signaling system. The recent advances in the understanding of the neurobiological basis of alcoholism suggest that the pharmacological and behavioral effects of EtOH are mediated through its action on neuronal signal transduction pathways and ligand-gated ion channels, receptor systems, and receptors that are coupled to G-proteins. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB1 receptor) that was activated by Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. To date, two fatty acid derivatives identified to be arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) have been isolated from both nervous and peripheral tissues. Both these compounds have been shown to mimic the pharmacological and behavioral effects of Delta(9)-THC. The involvement of the endocannabinoid signaling system in the development of tolerance to the drugs of abuse including EtOH has not been known until recently. Recent studies from our laboratory have demonstrated for the first time the down-regulation of CB1 receptor function and its signal transduction by chronic EtOH. The observed down-regulation of CB1 receptor binding and its signal transduction results from the persistent stimulation of the receptors by the endogenous CB1 receptor agonists, AEA and 2-AG, the synthesis of which has been found to be increased by chronic EtOH treatment. This enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid EtOH intake, have significantly reduced brain-CB1-receptor function consistent with other studies, where the CB1 receptor antagonist SR141716A has been shown to block voluntary EtOH intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 receptor gene in excessive EtOH drinking behavior and development of alcoholism. Ongoing investigations may lead to the development of potential therapeutic strategies for the treatment of alcoholism.
authors.affiliation: Division of Analytical Psychopharmacology, New York State Psychiatric Institute, New York, NY, USA. Basavaraj@nki.rfmh.org
authors.forename: B S
authors.initials: BS
authors.lastname: Basavarajappa
authors.forename: B L
authors.initials: BL
authors.lastname: Hungund
mesh_terms: D000437:Alcoholism / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism / Q000494:pharmacology*; D013759:Dronabinol / Q000494:pharmacology; D015777:Eicosanoids / Q000378:metabolism / Q000494:pharmacology*; D063388:Endocannabinoids; D000431:Ethanol / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D015777:Eicosanoids; D063388:Endocannabinoids; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000431:Ethanol; D013759:Dronabinol; D020962:Heterotrimeric GTP-Binding Proteins