Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement
Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement
复制标题
DOI：
10.1007/s00213-010-2127-x
复制
发表时间：
2011-05-01
影响因子：
3.4
通讯作者：
Galici, Ruggero
中科院分区：
文献类型：
--
作者：
Shoblock, James R.;Welty, Natalie;Galici, Ruggero
食欲素-1受体拮抗剂已显示阻断滥用药物和食物的强化作用。然而，阻断食欲素-2受体是否具有类似的作用尚未确定。我们最近描述了JNJ-10397049（一种选择性和脑渗透性食欲素-2受体拮抗剂）的体外和体内效应，这些研究的目的是评价JNJ-10397049全身给药是否阻断乙醇的奖励效应并逆转啮齿动物的乙醇戒断。作为比较，SB-408124，一种选择性食欲素-1受体拮抗剂，也进行了评估。大鼠训练口服自我管理乙醇（8%v/v）或糖精（0.1%v/v）在固定比例3强化计划。另一组大鼠接受乙醇（8% v/v）流质饮食，停药后4 h评价戒断体征。此外，乙醇诱导的细胞外多巴胺水平的增加，在脑桥核进行了测试。在单独的实验中，在小鼠中评价了条件性位置偏爱（CPP）的获得、表达和恢复。我们的结果表明，JNJ-10397049（1、3和10 mg/kg，sc）剂量依赖性地减少了大鼠的乙醇自我给药，而没有改变糖精自我给药、多巴胺水平或戒断体征。JNJ-10397049（10 mg/kg，sc）给药可减弱小鼠中乙醇CPP和乙醇诱导的活动过度的获得、表达和恢复。令人惊讶的是，SB-408124（3、10和30 mg/kg，sc）在这些程序中没有任何作用。
Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist.The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated.Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4 h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice.Our results indicate that JNJ-10397049 (1, 3, and 10 mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10 mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30 mg/kg, sc) did not have any effect in these procedures.Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.