Giuliano Chiara, Goodlett Charles R, Economidou Daina, García-Pardo Maria P, Belin David, Robbins Trevor W, Bullmore Edward T, Everitt Barry J
Behavioral and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.
Department of Psychology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA.
Neuropsychopharmacology. 2015 Dec;40(13):2981-92. doi: 10.1038/npp.2015.152. Epub 2015 Jun 5.
Distinct environmental and conditioned stimuli influencing ethanol-associated appetitive and consummatory behaviors may jointly contribute to alcohol addiction. To develop an effective translational animal model that illuminates this interaction, daily seeking responses, maintained by alcohol-associated conditioned stimuli (CSs), need to be dissociated from alcohol drinking behavior. For this, we established a procedure whereby alcohol seeking maintained by alcohol-associated CSs is followed by a period during which rats have the opportunity to drink alcohol. This cue-controlled alcohol-seeking procedure was used to compare the effects of naltrexone and GSK1521498, a novel selective μ-opioid receptor antagonist, on both voluntary alcohol-intake and alcohol-seeking behaviors. Rederived alcohol-preferring, alcohol-nonpreferring, and high-alcohol-drinking replicate 1 line of rats (Indiana University) first received 18 sessions of 24 h home cage access to 10% alcohol and water under a 2-bottle choice procedure. They were trained subsequently to respond instrumentally for access to 15% alcohol under a second-order schedule of reinforcement, in which a prolonged period of alcohol-seeking behavior was maintained by contingent presentations of an alcohol-associated CS acting as a conditioned reinforcer. This seeking period was terminated by 20 min of free alcohol drinking access that achieved significant blood alcohol concentrations. The influence of pretreatment with either naltrexone (0.1-1-3 mg/kg) or GSK1521498 (0.1-1-3 mg/kg) before instrumental sessions was measured on both seeking and drinking behaviors, as well as on drinking in the 2-bottle choice procedure. Naltrexone and GSK1521498 dose-dependently reduced both cue-controlled alcohol seeking and alcohol intake in the instrumental context as well as alcohol intake in the choice procedure. However, GSK1521498 showed significantly greater effectiveness than naltrexone, supporting its potential use for promoting abstinence and preventing relapse in alcohol addiction.
影响与乙醇相关的食欲和消费行为的不同环境和条件刺激可能共同导致酒精成瘾。为了开发一种有效的转化动物模型来阐明这种相互作用，需要将由酒精相关条件刺激（CSs）维持的每日寻求反应与酒精饮用行为区分开来。为此，我们建立了一种程序，即由酒精相关CSs维持的酒精寻求行为之后是一段大鼠有机会饮酒的时期。这种线索控制的酒精寻求程序被用来比较纳曲酮和新型选择性μ-阿片受体拮抗剂GSK1521498对自愿酒精摄入和酒精寻求行为的影响。重新衍生的酒精偏好、非酒精偏好和高酒精饮用复制1系大鼠（印第安纳大学）首先在2瓶选择程序下接受18次为期24小时的在家笼中接触10%酒精和水的实验。随后，它们在二级强化程序下接受训练，以通过工具性反应获得15%的酒精，在该程序中，酒精相关CSs作为条件强化物的偶然呈现维持了长时间的酒精寻求行为。这个寻求时期通过20分钟的自由饮酒结束，这导致了显著的血液酒精浓度。在工具性实验之前，测量了纳曲酮（0.1 - 1 - 3 mg/kg）或GSK1521498（0.1 - 1 - 3 mg/kg）预处理对寻求和饮用行为以及2瓶选择程序中饮酒的影响。纳曲酮和GSK1521498剂量依赖性地减少了工具性情境下线索控制的酒精寻求和酒精摄入以及选择程序中的酒精摄入。然而，GSK1521498显示出比纳曲酮显著更高的有效性，支持了其在促进戒酒和预防酒精成瘾复发方面的潜在用途。
