Carisbamate, a novel antiepileptic candidate compound, attenuates alcohol intake in alcohol-preferring rats.
Carisbamate, a novel antiepileptic candidate compound, attenuates alcohol intake in alcohol-preferring rats.
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Carisbamate 是一种新型抗癫痫候选化合物，可减少嗜酒大鼠的酒精摄入量。
DOI：
10.1111/j.1530-0277.2009.00966.x
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Levin,EdwardD
中科院分区：
文献类型：
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作者：
Rezvani,AmirH;Overstreet,DavidH;Vaidya,AnilH;Zhao,Boyu;Levin,EdwardD
背景：自1994年纳曲酮（Revia®）被FDA批准用于酒精中毒治疗以来，只有另外两种药物（Campral®和Topamax®）被批准用于酒精中毒治疗。然而，各种实验药物，包括抗癫痫药物，已经在动物模型和人类身上进行了测试，并取得了一些有希望的结果。本项目的目的是研究新型神经调节剂carisbamate（一种用于癫痫治疗的药物）对选择性饲养的酒精偏好大鼠酒精摄入量的影响。方法：使用2瓶选择程序，允许雄性偏好酒精的自交系P大鼠自由饮水或酒精（10%,v/v）。在确定了酒精和水摄入量的稳定基线后，评估了口服carisbamate（0、10、30、45、60和90 mg/kg）的急性效应。然后，在另一组雄性P大鼠中评估该化合物（60 mg/kg/天，连续14天）对酒精摄入量的慢性影响。在另一组实验中，比较了carisbamate和纳曲酮对酒精戒断引起的饮酒增加（一种渴望指数）的影响。将大鼠从酒精中撤出24小时，在重新暴露于酒精前30分钟给予载药、20 mg/kg纳曲酮或60 mg/kg氨基甲酸酯。酒精再暴露后6小时测量酒精和水的摄入量。为了确定carisbamate对糖精偏好的影响，研究人员让大鼠选择两瓶水和2%糖精溶液。然后，测定最高剂量carisbamate （90 mg/kg）、纳曲酮（20 mg/kg）和载药对糖精偏好的影响。结果：我们的研究结果显示，急性口服carisbamate后，酒精偏好P大鼠的酒精摄入量和偏好有选择性剂量依赖性减少。食物和水的摄入量没有明显的影响。长期服用carisbamate可显著降低最初的酒精摄入量和偏好，但在第10次治疗后产生部分耐受性。耐受性发展程度低于纳曲酮。在一段时间的酒精剥夺后，急性给予carisbamate比纳曲酮更有效地减少增加的酒精摄入量。与对照组相比，carisbamate和纳曲酮对糖的摄入量和偏好均无显著影响。结论：新型神经调节剂氨基甲酸酯对酒精摄入及相关措施有良好的影响，应考虑用于人体酒精中毒试验。
Background:Since 1994, when naltrexone (Revia®) was approved by the FDA for the treatment of alcoholism, only 2 other drugs (Campral®and Topamax®) have been approved for alcoholism treatment. However, various experimental drugs, including antiepileptic medications, have been tested in both animal models and in humans with some promising results. The purpose of this project was to study the effect of the novel neuromodulator carisbamate, which is in development for epilepsy treatment, on alcohol intake in selectively bred alcohol‐preferring rats.Methods:Male alcohol‐preferring inbred P rats were allowed to freely drink water or alcohol (10%, v/v) using a 2‐bottle choice procedure. After stable baselines for alcohol and water intakes were established, the acute effects of oral carisbamate (0, 10, 30, 45, 60, and 90 mg/kg) were assessed. Then, the chronic effect of the compound (60 mg/kg/day for 14 consecutive days) on alcohol intake was assessed in a separate group of male P rats. In another set of experiments, the effects of carisbamate and naltrexone on alcohol withdrawal‐induced elevated drinking of alcohol, an index of craving, were compared. Rats were withdrawn from alcohol for 24 hours and were given vehicle, 20 mg/kg naltrexone or 60 mg/kg carisbamate 30 minutes before re‐exposure to alcohol. Alcohol and water intake was measured 6 hours after alcohol re‐exposure. To determine the effects of carisbamate on saccharin preference, rats were put on a 2‐bottle choice of water versus a solution of 2% saccharin. Then, the effect of the highest dose of carisbamate (90 mg/kg) and naltrexone (20 mg/kg) and the vehicle on saccharin preference was determined.Results:Our results showed that there was a selective dose‐dependent reduction in alcohol intake and preference in the alcohol‐preferring P rat after an acute oral administration of carisbamate. There were no significant effects on food or water intake. Chronic administration of carisbamate significantly reduced alcohol intake and preference initially, but partial tolerance developed after the 10th treatment. The degree of tolerance development was less than that observed for naltrexone. Acute administration of carisbamate was more effective than naltrexone in reducing enhanced alcohol intake after a period of alcohol deprivation.Compared with control vehicle neither carisbamate nor naltrexone had a significant effect on saccharin intake and preference.Conclusion:The novel neuromodulator compound carisbamate has a favorable profile of effects on alcohol intake and related measures and should be considered for testing on human alcoholics.