Hungund B L, Basavarajappa B S
Division of Analytical Psychopharmacology, New York State Psychiatric Institute, College of Physicians and Surgeons, Columbia University, New York, NY 100032, USA.
Alcohol Alcohol. 2000 Mar-Apr;35(2):126-33. doi: 10.1093/alcalc/35.2.126.
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 delta-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 (CB(1)) and mimic many of the pharmacological and behavioural effects of THC including tolerance development. The role of endocannabinoids and the CB(1) 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-CB(1) receptor signal transduction system. Recent studies have shown that chronic EtOH exposure produces downregulation of CB(1) receptors and an inhibition of CB(1) receptor agonist-stimulated GTPgammaS binding in mouse brain synaptic plasma membranes (SPM). The observed receptor downregulation results from the persistent stimulation of the receptors by the endogenous CB(1) receptor agonist AnNH, the synthesis of which is increased by chronic EtOH exposure. Further, the CB(1) 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.
在阐明参与乙醇（EtOH）耐受性和依赖性发展的神经元第二信使途径中的分子和细胞变化方面已经取得了重大进展。长期接触EtOH已被证明会影响神经元信号转导的多个方面以及配体门控离子通道和受体系统，包括与GTP结合调节蛋白（G蛋白）超家族偶联的受体。最近发现一种由大麻的主要精神活性成分δ-9-四氢大麻酚（THC）激活的G蛋白偶联受体，从而发现了内源性激动剂。在哺乳动物大脑中发现的一种这样的激动剂被鉴定为花生四烯酸（AA）代谢物，并被命名为花生四烯乙醇胺（AnNH）。AnNH已被证明能特异性结合大麻素受体（CB(1)），并模拟THC的许多药理和行为效应，包括耐受性发展。直到最近才开始探索内源性大麻素和CB(1)受体信号转导系统在药物滥用耐受性发展中的作用。本综述中提出的研究结果首次提供了证据，表明EtOH的一些药理作用，包括耐受性发展，可能通过内源性大麻素-CB(1)受体信号转导系统的参与来介导。最近的研究表明，慢性EtOH暴露会导致CB(1)受体下调，并抑制小鼠脑突触质膜（SPM）中CB(1)受体激动剂刺激的GTPγS结合。观察到的受体下调是由于内源性CB(1)受体激动剂AnNH对受体的持续刺激，而慢性EtOH暴露会增加AnNH的合成。此外，CB(1)受体拮抗剂SR-141716A已被证明能阻断大鼠和小鼠的自愿EtOH摄入。基于这些研究，提出了一个假设来解释内源性大麻素系统可能参与EtOH的药理和行为效应。
