Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice.
Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice.
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DOI：
10.1016/j.neuropharm.2016.08.008
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发表时间：
2016-11
影响因子：
4.7
通讯作者：
Hopf FW
中科院分区：
文献类型：
--
作者：
Lei K;Wegner SA;Yu JH;Hopf FW
成瘾是由成瘾物质的病理性动机促进的，尽管做出了广泛的努力，酒精使用障碍（AUD）继续造成非常高的社会，身体和经济损失。强迫性饮酒，即使酒精伴随着负面后果，也会持续消费，被认为是治疗AUD的一个特殊障碍。啮齿类动物的厌恶性酒精摄入，例如，即使酒精与苦味剂奎宁配对，啮齿类动物也会饮酒，已被认为是人类酒精消费的一些强迫性方面的模型。然而，驱动强迫性饮酒的关键机制才刚刚开始被确定。神经肽食欲素与可卡因、偏好食物和酒精的高动机有关。因此，我们研究了食欲素受体在强迫性饮酒中的作用，其中C57 BL/6小鼠每天2小时摄入15%酒精，含或不含奎宁（100 µM）。我们发现，广泛使用的选择性食欲素-1受体（OX 1 R）阻滞剂SB-334867（SB）的全身给药，在剂量低于减少无奎宁酒精摄入量的情况下，显著减少了强迫性消费。特别是，3 mg/kg SB的剂量仅抑制了强迫性饮酒。此外，SB没有减少饮酒期间的并发水摄入量，也没有改变糖精+奎宁的摄入量。此外，OX 2 R拮抗剂TCS-OX 2 -29（3或10 mg/kg）未改变含或不含奎宁的酒精摄入量。总之，我们的研究结果表明，OX 1 R信号对于促进强迫性饮酒特别重要，OX 1 R可能代表一种新的治疗方法来对抗人类AUD的强迫性方面。
Addiction is promoted by pathological motivation for addictive substances, and, despite extensive efforts, alcohol use disorders (AUDs) continue to extract a very high social, physical, and economic toll. Compulsive drinking of alcohol, where consumption persists even when alcohol is paired with negative consequences, is considered a particular obstacle for treating AUDs. Aversion-resistant alcohol intake in rodents, e.g. where rodents drink even when alcohol is paired with the bitter tastant quinine, has been considered to model some compulsive aspects of human alcohol consumption. However, the critical mechanisms that drive compulsive-like drinking are only beginning to be identified. The neuropeptide orexin has been linked to high motivation for cocaine, preferred foods, and alcohol. Thus, we investigated the role of orexin receptors in compulsive-like alcohol drinking, where C57BL/6 mice had 2-hr daily access to 15% alcohol with or without quinine (100 µM). We found that systemic administration of the widely used selective orexin-1 receptor (OX1R) blocker, SB-334867 (SB), significantly reduced compulsive-like consumption at doses lower than those reported to reduce quinine-free alcohol intake. The dose of 3-mg/kg SB, in particular, suppressed only compulsive-like drinking. Furthermore, SB did not reduce concurrent water intake during the alcohol drinking sessions, and did not alter saccharin+quinine consumption. In addition, the OX2R antagonist TCS-OX2-29 (3 or 10 mg/kg) did not alter intake of alcohol with or without quinine. Together, our results suggest that OX1R signaling is particularly important for promoting compulsive-like alcohol drinking, and that OX1Rs might represent a novel therapy to counteract compulsive aspects of human AUDs.
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影响因子：
4.3
作者：
Anderson RI;Becker HC;Adams BL;Jesudason CD;Rorick-Kehn LM
通讯作者：
Rorick-Kehn LM
影响因子：
3
作者：
Brown JA;Woodworth HL;Leinninger GM
通讯作者：
Leinninger GM
影响因子：
5.5
作者：
Bouchery, Ellen E.;Harwood, Henrick J.;Brewer, Robert D.
通讯作者：
Brewer, Robert D.
影响因子：
5.3
作者：
Barbier, Estelle;Tapocik, Jenica D.;Heilig, Markus
通讯作者：
Heilig, Markus
影响因子：
3.4
作者：
Brown, Robyn Mary;Kim, Andrezza K.;Lawrence, Andrew John
通讯作者：
Lawrence, Andrew John