Basavarajappa Balapal S, Hungund Basalingappa L
Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Alcohol Alcohol. 2005 Jan-Feb;40(1):15-24. doi: 10.1093/alcalc/agh111. Epub 2004 Nov 18.
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 (CB(1) receptor), which was activated by Delta(9)-tetrahydrocannabinol (Delta(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 Delta(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 CB(1) receptors and its signal transduction. The observed downregulation of CB(1) 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 CB(1) receptor function in the brain, consistent with other studies in which the CB(1) receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB(1) receptor system promoted alcohol craving, suggesting a role for the CB(1) 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.
本综述评估了内源性大麻素系统在酒精耐受性发展中所起作用的证据。一种由大麻中的主要精神活性成分Δ⁹-四氢大麻酚（Δ⁹-THC）激活的G蛋白偶联受体，即大麻素受体（CB₁受体）的鉴定，促使了内源性大麻素激动剂的发现。到目前为止，已从神经组织和外周组织中分离出四种脂肪酸衍生物，分别为花生四烯酸乙醇胺（AEA）、2-花生四烯酸甘油（2-AG）、2-花生四烯酸甘油醚（诺拉地因醚）和维罗达姆因。AEA和2-AG均已被证明可模拟Δ⁹-THC的药理和行为效应。直到最近，内源性大麻素系统在酒精耐受性发展中的作用才为人所知。我们实验室最近的研究首次表明内源性大麻素系统在酒精耐受性发展中发挥作用。慢性酒精处理已被证明会下调CB₁受体及其信号转导。观察到的CB₁受体功能下调是由于AEA和2-AG对受体的持续刺激所致，慢性酒精处理已证明会增加其合成。内源性大麻素形成的增强可能随后影响神经递质的释放。研究发现，已知会避免摄入酒精的DBA/2小鼠大脑中的CB₁受体功能显著降低，这与其他研究结果一致，即在这些研究中，CB₁受体拮抗剂SR 141716A已被证明可阻断啮齿动物的自愿酒精摄入。同样，CB₁受体系统的激活促进了对酒精的渴望，这表明CB₁受体基因在过度饮酒行为和酒精中毒发展中起作用。正在进行的研究可能会使人们更好地理解酒精耐受性发展的潜在机制，并开发出治疗酒精中毒的治疗策略。
