Schulteis G, Hyytiä P, Heinrichs S C, Koob G F
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Alcohol Clin Exp Res. 1996 Feb;20(1):164-71. doi: 10.1111/j.1530-0277.1996.tb01060.x.
The study of alcohol abuse traditionally has placed great emphasis on the development of tolerance and dependence as key factors. However, animal models of ethanol self-administration in dependent rats have been difficult to establish, caused in part by ethanol's aversive taste cues and subsequent aversive effects (i.e., "hangover" malaise) that prevent substantial ethanol consumption. In this study, this problem was addressed in animals trained to self-administer ethanol (10% w/v) in a sweetened-solution fading procedure before induction of dependence and repeated exposure to withdrawal. Once stable rates of responding for ethanol were achieved, a palatable liquid diet containing 8.7% (v/v) ethanol was introduced as the sole source of calories and fluid for one group of rats [ethanol diet (ED) group]. A second group of rats received a control diet with sucrose isocalorically substituted for ethanol (CD group). After 14-17 days of liquid diet exposure, the rats were withdrawn once a week for 4 weeks and 8 hr into each withdrawal session were allowed to self-administer ethanol or water for 60 min. As compared with CD rats, ED rats showed significantly greater intake of ethanol, but not water. No significant differences were found when separate groups of ED/CD rats were allowed to self-administer an alternate reinforcer (0.0075% saccharin solution). Rats who consistently had blood alcohol levels (BALs) above 100 mg% at the time of withdrawal sustained high levels of ethanol self-administration throughout the four withdrawal sessions. In contrast, rats who had an average BAL at withdrawal below 100 mg% showed progressive decreases in ethanol self-administration during repeated withdrawal episodes. The results demonstrated that chronic exposure to ethanol and repeated periods of abstinence are accompanied by elevated rates of ethanol intake in certain animals, and the persistence of elevated self-administration behavior of individual rats is predicted by their BAL at the time of withdrawal.
传统上,对酒精滥用的研究非常重视耐受性和依赖性的发展,将其视为关键因素。然而,在依赖大鼠中建立乙醇自我给药的动物模型一直很困难,部分原因是乙醇的厌恶味觉线索以及随后的厌恶效应(即“宿醉”不适)会阻止大量摄入乙醇。在本研究中,通过在诱导依赖性和反复暴露于戒断之前,让动物在甜味溶液消退程序中自我给药乙醇(10% w/v)来解决这个问题。一旦实现了对乙醇稳定的反应率,就为一组大鼠引入一种含有8.7%(v/v)乙醇的可口液体饮食作为唯一的热量和液体来源[乙醇饮食(ED)组]。第二组大鼠接受用蔗糖等热量替代乙醇的对照饮食(CD组)。在液体饮食暴露14 - 17天后,大鼠每周戒断一次,共4周,每次戒断期间允许大鼠在8小时内自我给药乙醇或水60分钟。与CD大鼠相比,ED大鼠的乙醇摄入量显著更高,但水的摄入量没有显著差异。当分别让ED/CD大鼠组自我给药另一种强化物(0.0075%糖精溶液)时,未发现显著差异。在戒断时血液酒精水平(BAL)持续高于100 mg%的大鼠在整个四次戒断期间维持了较高水平的乙醇自我给药。相比之下,在戒断时平均BAL低于100 mg%的大鼠在反复戒断期间乙醇自我给药量逐渐减少。结果表明,长期接触乙醇和反复戒断会使某些动物的乙醇摄入量增加,并且个体大鼠自我给药行为升高的持续性可由其戒断时的BAL预测。