Roles for the endocannabinoid system in ethanol-motivated behavior.
Roles for the endocannabinoid system in ethanol-motivated behavior.
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DOI：
10.1016/j.pnpbp.2015.06.011
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发表时间：
2016-02-04
影响因子：
5.6
通讯作者：
Morgan DJ
中科院分区：
文献类型：
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作者：
Henderson-Redmond AN;Guindon J;Morgan DJ
酒精使用障碍是一个严重的人类健康问题，导致大量的人类生命损失和社会经济成本。目前可用的治疗方案不能充分解决这一人类健康问题，因此，迫切需要其他疗法。内源性大麻素系统已被证明，使用动物模型，以调节乙醇动机的行为，它也已被证明，慢性乙醇暴露可能对内源性大麻素系统具有潜在的长期影响。例如，在细胞培养或临床前啮齿动物模型中，长期暴露于乙醇会导致内源性大麻素水平增加，导致大麻素受体1（CB 1）下调，并使该受体与下游G蛋白信号传导途径解偶联。使用正电子发射断层扫描（PET），在人类酒精患者的大脑多个区域中发现了类似的CB 1下调。在啮齿类动物中，CB 1反向激动剂SR 141716 A（利莫那班）治疗或CB 1基因缺失导致自愿饮酒减少，乙醇刺激的多巴胺在丘脑核中释放，乙醇的操作性自我给药，对乙醇运动效应的敏感性，以及乙醇动机行为的恢复/复发。尽管由于负面的神经精神副作用，利莫那班或CB 1的其他拮抗剂/反向激动剂的临床用途受到限制，但CB 1的负变构调节剂和内源性大麻素分解代谢抑制剂代表了值得进一步研究的治疗靶点。
Alcohol use disorder represents a significant human health problem that leads to substantial loss of human life and financial cost to society. Currently available treatment options do not adequately address this human health problem, and thus, additional therapies are desperately needed. The endocannabinoid system has been shown, using animal models, to modulate ethanol-motivated behavior, and it has also been demonstrated that chronic ethanol exposure can have potentially long-lasting effects on the endocannabinoid system. For example, chronic exposure to ethanol, in either cell culture or preclinical rodent models, causes an increase in endocannabinoid levels that results in down-regulation of the cannabinoid receptor 1 (CB1) and uncoupling of this receptor from downstream G protein signaling pathways. Using positron emission tomography (PET), similar down-regulation of CB1 has been noted in multiple regions of the brain in human alcoholic patients. In rodents, treatment with the CB1 inverse agonist SR141716A (Rimonabant), or genetic deletion of CB1 leads to a reduction in voluntary ethanol drinking, ethanol-stimulated dopamine release in the nucleus accumbens, operant self-administration of ethanol, sensitization to the locomotor effects of ethanol, and reinstatement/relapse of ethanol-motivated behavior. Although the clinical utility of Rimonabant or other antagonists/inverse agonists for CB1 is limited due to negative neuropsychiatric side effects, negative allosteric modulators of CB1 and inhibitors of endocannabinoid catabolism represent therapeutic targets worthy of additional examination.