γ-氨基丁酸B(GABAB)受体激动剂巴氯芬在两种过量饮酒小鼠模型中的双向对映体选择性作用。
Bidirectional enantioselective effects of the GABAB receptor agonist baclofen in two mouse models of excessive ethanol consumption.
作者信息
Kasten Chelsea R, Blasingame Shelby N, Boehm Stephen L
机构信息
Department of Psychology, Indianapolis University - Purdue University Indianapolis, 402 N. Blackford St., LD 124, Indianapolis, IN 46202, USA.
Department of Psychology, Indianapolis University - Purdue University Indianapolis, 402 N. Blackford St., LD 124, Indianapolis, IN 46202, USA.
出版信息
Alcohol. 2015 Feb;49(1):37-46. doi: 10.1016/j.alcohol.2014.11.005. Epub 2014 Dec 17.
The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption. The first was a Drinking-in-the-Dark procedure that provides "binge-like" ethanol access to mice by restricting access to a 2-h period, 3 h into the dark cycle. The second was a two-bottle choice procedure that utilized selectively bred High Alcohol Preferring 1 (HAP1) mice to model chronic ethanol access. HAP1 mice are selectively bred to consume pharmacologically relevant amounts of ethanol in a 24-h two-bottle choice paradigm. The results showed that baclofen yields enantioselective effects on ethanol intake in both models, and that these effects are bidirectional. Total ethanol intake was decreased by R(+)-baclofen, while total intake was increased by S(-)-baclofen in the binge-like and chronic drinking models. Whereas overall binge-like saccharin intake was significantly reduced by R(+)-baclofen, chronic intake was not significantly altered. S(-)-baclofen did not significantly alter saccharin intake. Neither enantiomer significantly affected locomotion during binge-like reinforcer consumption. Collectively, these results demonstrate that baclofen produces enantioselective effects on ethanol consumption. More importantly, the modulation of consumption is bidirectional. The opposing enantioselective effects may explain some of the variance seen in published baclofen literature.
γ-氨基丁酸B(GABAB)受体激动剂巴氯芬已在酒精使用障碍的临床前模型中得到广泛研究,但其疗效结果尚不确定。临床上使用的消旋巴氯芬可分解为该药物的单独对映体。巴氯芬已被证明在行为试验中产生对映体选择性效应,包括那些模拟反射性行为和性行为的试验。目前的研究旨在表征巴氯芬在两种不同的乙醇消耗模型中的对映体选择性效应。第一个是黑暗中饮酒程序,通过将饮酒时间限制在黑暗周期开始3小时后的2小时内,使小鼠能够“暴饮”乙醇。第二个是双瓶选择程序,利用选择性培育的高酒精偏好1型(HAP1)小鼠来模拟长期接触乙醇的情况。HAP1小鼠是经过选择性培育的,在24小时双瓶选择模式下会摄入药理学相关量的乙醇。结果表明,巴氯芬在两种模型中对乙醇摄入量均产生对映体选择性效应,且这些效应是双向的。在暴饮样和长期饮酒模型中,R(+)-巴氯芬可降低乙醇总摄入量,而S(-)-巴氯芬则会增加总摄入量。虽然R(+)-巴氯芬可显著降低总体暴饮样糖精摄入量,但长期摄入量没有显著改变。S(-)-巴氯芬没有显著改变糖精摄入量。在暴饮样强化物消耗期间,两种对映体均未显著影响运动能力。总体而言,这些结果表明巴氯芬对乙醇消耗产生对映体选择性效应。更重要的是,对消耗量的调节是双向的。相反的对映体选择性效应可能解释了已发表的巴氯芬文献中出现的一些差异。