Blockade of alcohol escalation and "relapse" drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice.
Blockade of alcohol escalation and "relapse" drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice.
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在雄性和雌性 C57BL/6J 小鼠中通过药理学 FAAH 抑制来阻止酒精升高和“复发”饮酒。
DOI：
10.1007/s00213-017-4691-9
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发表时间：
2017
影响因子：
3.4
通讯作者：
Kreek,MaryJeanne
中科院分区：
文献类型：
--
作者：
Zhou,Yan;Schwartz,BenjaminI;Giza,Joanna;Gross,StevenS;Lee,FrancisS;Kreek,MaryJeanne
研究背景花生四烯酸酰胺（Anandamide，AEA）依赖的信号转导受分解代谢酶脂肪酸酰胺水解酶（fatty acid amide hydrolase，FAAH）的调控.有证据表明，FAAH和AEA参与了酒精的行为效应。因此，我们调查是否选择性FAAH抑制剂，URB 597（环己基氨基甲酸3′-[氨基羰基]-[1，1 ′-联苯]-3-基酯），改变酒精摄入量的小鼠在自愿酒精drinking model.MethodsMice，进行3周的慢性间歇性访问（IA）在两瓶的选择范例与24小时访问每隔一天，开发快速升级的酒精摄入量和高偏好。我们使用酒精剥夺效应（ADE）模型评估了URB 597从慢性IA急性（1天）戒断和1周戒断后的药理作用。AEA和N-酰基乙醇酰胺（NAE）的丰度测定后，慢性IA，急性（1天），或长期（1和2周）退出在4个脑regions.ResultsUrB597急性预处理减少酒精摄入量和偏好后，急性退出。这种作用可通过使用选择性1型大麻素受体（CB 1）拮抗剂预处理来阻断，这表明CB 1介导的机制。有效剂量URB 597的单次和多次给药方案均预防了ADE，多次给药方案后未出现耐受性。AEA和NAE水平在急性戒断后测量的所有脑区短暂增加，表明内源性大麻素系统参与急性酒精戒断应激反应.ConclusionFAAH抑制剂减少酒精升级和“复发”饮酒小鼠。
BackgroundAnandamide (AEA)-dependent signaling is regulated by the catabolic enzyme fatty acid amide hydrolase (FAAH). Several lines of evidence have demonstrated that FAAH and AEA are involved in the behavioral effects of alcohol. Therefore, we investigated whether a selective FAAH inhibitor, URB597 (cyclohexylcarbamic acid 3′-[aminocarbonyl]-[1,1′-biphenyl]-3-yl ester), altered alcohol intake in mice in a voluntary alcohol drinking model.MethodsMice, subjected to 3 weeks of chronic intermittent access (IA) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We evaluated the pharmacological effects of URB597 after both acute (1-day) withdrawal from chronic IA and 1-week withdrawal using the alcohol deprivation effect (ADE) model. AEA andN-acyl ethanolamide (NAE) abundances were determined after chronic IA, acute (1-day), or long-term (1 and 2 weeks) withdrawal in four brain regions.ResultsAcute pretreatment with URB597 reduced alcohol intake and preference after acute withdrawal. This effect was blocked by pretreatment with a selective type 1 cannabinoid receptor (CB1) antagonist, suggesting a CB1-mediated mechanism. Both single- and multiple-dosing regimens with an effective dose of URB597 prevented the ADE, with no tolerance development after the multi-dosing regimen. AEA and NAE levels were transiently increased in all brain regions measured after acute withdrawal, indicating that the endocannabinoid system is involved in acute alcohol withdrawal stress response.ConclusionFAAH inhibitors reduce alcohol escalation and “relapse” drinking in mice.