Role of endocannabinoids in alcohol consumption and intoxication: Studies of mice lacking fatty acid amide hydrolase
Role of endocannabinoids in alcohol consumption and intoxication: Studies of mice lacking fatty acid amide hydrolase
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DOI：
10.1038/sj.npp.1301274
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发表时间：
2007-07-01
影响因子：
7.6
通讯作者：
Harris, R. Adron
中科院分区：
文献类型：
--
作者：
Blednov, Yuri A.;Cravatt, Benjamin F.;Harris, R. Adron
内源性大麻素信号在乙醇摄入的调节中起着重要作用。脂肪酸酰胺水解酶(FAAH)是包括花生胺在内的内源性大麻素代谢的关键膜蛋白，阻断FAAH可增加脑组织花生胺的水平。为了确定FAAH是否调节酒精消耗，我们研究了FAAH基因缺失的突变小鼠。与野生型小鼠相比，零突变小鼠表现出更高的酒精偏好，并自愿消费更多的酒精。甜味或苦味溶液的摄入量没有显著差异。为了确定FAAH对酒精摄入的特异性，我们研究了其他与酒精相关的行为。在酒精诱导的急性戒断程度、对酒精的条件性味觉厌恶、条件性位置偏爱或对酒精催眠效应的敏感性方面，零突变小鼠与野生型小鼠没有差异。然而，低剂量乙醇(3.2和3.4g/kg)引起的翻正反射消失的持续时间较短，而从乙醇引起的运动不协调中恢复较快。在突变小鼠中看到的所有三种行为表型(对乙醇的偏好增加，对乙醇诱导的镇静的敏感性降低，以及从乙醇引起的运动不协调中更快地恢复)都通过注射FAAH活性的特定抑制剂-URB597在野生型小鼠中复制。这些数据表明，由于急性乙醇中毒的减少，内源性大麻素信号的增加增加了乙醇的消耗。
Endocannabinoid signaling plays the important role in regulation of ethanol intake. Fatty acid amide hydrolase ( FAAH) is a key membrane protein for metabolism of endocannabinoids, including anandamide, and blockade of FAAH increases the level of anandamide in the brain. To determine if FAAH regulates ethanol consumption, we studied mutant mice with deletion of the FAAH gene. Null mutant mice showed higher preference for alcohol and voluntarily consumed more alcohol than wild-type littermates. There was no significant difference in consumption of sweet or bitter solutions. To determine the specificity of FAAH for ethanol intake, we studied additional ethanol-related behaviors. There were no differences between null mutant and wild-type mice in severity of ethanol-induced acute withdrawal, conditioned taste aversion to alcohol, conditioned place preference, or sensitivity to hypnotic effect of ethanol. However, null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol. All three behavioral phenotypes ( increased preference for ethanol, decreased sensitivity to ethanol-induced sedation, and faster recovery from ethanol-induced motor incoordination) seen in mutant mice were reproduced in wild-type mice by injection of a specific inhibitor of FAAH activity-URB597. These data suggest that increased endocannabinoid signaling increased ethanol consumption owing to decreased acute ethanol intoxication.