Alcohol and Alcoholism Vol. 35, No. 2, pp. 126-133, 2000
© 2000 Medical Council on Alcoholism
Review
ARE ANANDAMIDE AND CANNABINOID RECEPTORS INVOLVED IN ETHANOL TOLERANCE? A REVIEW OF THE EVIDENCE
1 Division of Analytical Psychopharmacology, New York State Psychiatric Institute and
2 Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 100032, USA
Received 9 June 1999; first review notified 23 August 1999; accepted 7 October 1999
ABSTRACT
There have been significant developments towards the elucidation of molecular and cellular changes in neuronal second messenger pathways involved in the development of tolerance to and dependence on ethanol (EtOH). The long-term exposure to EtOH has been shown to affect several aspects of neuronal signal transduction as well as ligand-gated ion channels and receptor systems, including the receptors that are coupled to the superfamily of GTP binding regulatory proteins (G-proteins). The recent identification of a G-protein coupled receptor that was activated by 
-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, led to the discovery of endogenous agonists. One such agonist found to exist in mammalian brain was characterized to be an arachidonic acid (AA) metabolite and was named anandamide (AnNH). AnNH has been shown to bind specifically to the cannabinoid receptor (CB1) and mimic many of the pharmacological and behavioural effects of THC including tolerance development. The role of endocannabinoids and the CB1 receptor signal transduction system in tolerance development to drugs of abuse has not been explored until recently. The findings presented in this review provide evidence for the first time that some of the pharmacological actions of EtOH including tolerance development may be mediated through participation of the endocannabinoid–CB1 receptor signal transduction system. Recent studies have shown that chronic EtOH exposure produces downregulation of CB1 receptors and an inhibition of CB1 receptor agonist-stimulated GTP
S binding in mouse brain synaptic plasma membranes (SPM). The observed receptor downregulation results from the persistent stimulation of the receptors by the endogenous CB1 receptor agonist AnNH, the synthesis of which is increased by chronic EtOH exposure. Further, the CB1 receptor antagonist SR-141716A has been shown to block voluntary EtOH intake in rats and mice. Based on these studies, a hypothesis is presented to explain the possible involvement of the endocannabinoid system in the pharmacological and behavioural effects of EtOH.
Abbreviations: AA, arachidonic acid • AAPC, arachidonyl-PC • AnNH, anandamide • CB1, cannabinoid receptors • DA, dopamine • EtOH, ethanol • FAEE, fatty acid ethyl esters • LTP, long-term potentiation • NAE, N-acyl ethanolamide • NAPE, N-acyl ethanolamine • N-ArPE, N-arachidonylphosphatidylethanolamine • PC, phosphatidylcholine • PL, phospholipid • PLA2, phospholipase A2 • PLD, phospholipase D • PMSF, phenylmethylsulphonyl fluoride • PTX, pertussis toxin • SPM, synaptic plasma membranes • THC, tetrahydrocannabinol.
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