Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models.
Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models.
复制标题
DOI：
10.3389/fnins.2014.00033
复制
发表时间：
2014
影响因子：
4.3
通讯作者：
Rorick-Kehn LM
中科院分区：
文献类型：
--
作者：
Anderson RI;Becker HC;Adams BL;Jesudason CD;Rorick-Kehn LM
为了检查食欲素-1和食欲素-2受体活性对乙醇自我给药的作用，使用高饮酒啮齿动物模型在各种自我给药范例中评估差异靶向食欲素（OX）受体亚型的化合物。使用2瓶选择程序在乙醇偏好（P）大鼠中测试了OX 1拮抗剂SB 334867、OX 2拮抗剂LSN 2424100和混合OX 1/2拮抗剂Almorexant（ACT-078573）对家庭笼乙醇消耗的影响。在单独的实验中，SB 334867，LSN 2424100，和almorexant对操作性乙醇自我管理的影响进行了评估，在P大鼠维持在一个渐进的比例操作性强化计划。在第三系列实验中，将SB 334867、LSN 2424100和almorexant给予乙醇偏好的C57 BL/6 J小鼠，以检查OX受体阻断剂对暴饮暴食（在黑暗中饮酒）模型中乙醇摄入的影响。在P大鼠与慢性家庭笼自由选择乙醇访问，SB 334867和almorexant显着减少乙醇的摄入量，但almorexant也减少了水的摄入量，这表明非特异性的消费行为的影响。在渐进比例操作实验中，LSN 2424100和Almorexant降低了P大鼠的断点和乙醇消耗量，而Almorexant无活性对映体和SB 334867没有显著影响消耗乙醇的动机。正如预期的那样，注射溶媒的小鼠在黑暗中饮酒模型中表现出狂欢样饮酒模式。所有三种OX拮抗剂均降低了乙醇摄入量和相对于溶媒注射对照的血液乙醇浓度，但SB 334867和LSN 2424100也降低了不同小鼠队列中的蔗糖消耗，表明了非特异性作用。总的来说，这些结果有助于越来越多的证据表明，OX 1和OX 2受体活性影响乙醇自我管理，虽然效果可能不是选择性的乙醇消费。
To examine the role of orexin-1 and orexin-2 receptor activity on ethanol self-administration, compounds that differentially target orexin (OX) receptor subtypes were assessed in various self-administration paradigms using high-drinking rodent models. Effects of the OX1 antagonist SB334867, the OX2 antagonist LSN2424100, and the mixed OX1/2 antagonist almorexant (ACT-078573) on home cage ethanol consumption were tested in ethanol-preferring (P) rats using a 2-bottle choice procedure. In separate experiments, effects of SB334867, LSN2424100, and almorexant on operant ethanol self-administration were assessed in P rats maintained on a progressive ratio operant schedule of reinforcement. In a third series of experiments, SB334867, LSN2424100, and almorexant were administered to ethanol-preferring C57BL/6J mice to examine effects of OX receptor blockade on ethanol intake in a binge-like drinking (drinking-in-the-dark) model. In P rats with chronic home cage free-choice ethanol access, SB334867 and almorexant significantly reduced ethanol intake, but almorexant also reduced water intake, suggesting non-specific effects on consummatory behavior. In the progressive ratio operant experiments, LSN2424100 and almorexant reduced breakpoints and ethanol consumption in P rats, whereas the almorexant inactive enantiomer and SB334867 did not significantly affect the motivation to consume ethanol. As expected, vehicle-injected mice exhibited binge-like drinking patterns in the drinking-in-the-dark model. All three OX antagonists reduced both ethanol intake and resulting blood ethanol concentrations relative to vehicle-injected controls, but SB334867 and LSN2424100 also reduced sucrose consumption in a different cohort of mice, suggesting non-specific effects. Collectively, these results contribute to a growing body of evidence indicating that OX1 and OX2 receptor activity influences ethanol self-administration, although the effects may not be selective for ethanol consumption.
登录
查看更多内容
影响因子：
--
作者：
Mahler, Stephen V.;Smith, Rachel J.;Moorman, David E.;Sartor, Gregory C.;Aston-Jones, Gary
通讯作者：
Aston-Jones, Gary
影响因子：
2.3
作者：
Czachowski, CL;Santini, LA;Samson, HH
通讯作者：
Samson, HH
影响因子：
3.4
作者：
Shoblock, James R.;Welty, Natalie;Galici, Ruggero
通讯作者：
Galici, Ruggero
影响因子：
3.4
作者：
Richards, Jemma K.;Simms, Jeffrey A.;Steensland, Pia;Taha, Sharif A.;Borgland, Stephanie L.;Bonci, Antonello;Bartlett, Selena E.
通讯作者：
Bartlett, Selena E.
影响因子：
16.2
作者：
Borgland, SL;Taha, SA;Bonci, A
通讯作者：
Bonci, A