Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California, USA.
Alcohol Clin Exp Res. 2010 Sep 1;34(9):1565-73. doi: 10.1111/j.1530-0277.2010.01241.x. Epub 2010 Jun 25.
Continued consumption of alcohol despite deleterious consequences is a hallmark of alcoholism and represents a critical challenge to therapeutic intervention. Previous rat studies showed that enduring alcohol self-administration despite pairing alcohol with normally aversive stimuli was only observed after very long-term intake (>8 months). Aversion-resistant alcohol intake has been previously interpreted to indicate pathological or compulsive motivation to consume alcohol. However, given the time required to model compulsive alcohol seeking in previous studies, there is considerable interest in developing more efficient and quantitative rodent models of aversion-resistant alcohol self-administration.
Outbred Wistar rats underwent 3 to 4 months or approximately 1.5 months of intermittent, home-cage, two-bottle access (IAA) to 20% alcohol (v/v) or water. Then, after brief operant training, the effect of the bitter-tasting quinine (0.1 g/l) on the motivation to seek alcohol was quantified via progressive ratio (PR). Motivation for quinine-adulterated 2% sucrose under PR was assayed in a separate cohort of 3 to 4 months IAA rats. The effects of quinine on home-cage alcohol consumption in IAA rats and rats with continuous access to alcohol were also examined. Finally, a dose-response for quinine taste preference in IAA and continuous-access animals was determined.
Motivation for alcohol after 3 to 4 months IAA, measured using an operant PR procedure, was not altered by adulteration of alcohol with 0.1 g/l quinine. In contrast, after 3 to 4 months of IAA, motivation for sucrose under PR was significantly reduced by adulteration of sucrose with 0.1 g/l quinine. In addition, motivation for alcohol after only approximately 1.5 months IAA was significantly reduced by adulteration of alcohol with 0.1 g/l quinine. Furthermore, home-cage alcohol intake by IAA rats was insensitive to quinine at concentrations (0.01, 0.03 g/l) that significantly reduced alcohol drinking in animals with continuous access to alcohol. Finally, no changes in quinine taste preference after 3 to 4 months IAA or continuous access to alcohol were observed.
We have developed a novel and technically simple hybrid operant/IAA model in which quinine-resistant motivation for alcohol is evident after an experimentally tractable period of time (3 to 4 months vs. 8 months). Quinine dramatically reduced sucrose and water intake by IAA rats, indicating that continued responding for alcohol in IAA rats despite adulteration with the normally aversive quinine might reflect maladaptive or compulsive motivation for alcohol. This model could facilitate identification of novel therapeutic interventions for pathological alcohol seeking in humans.
尽管有害后果持续存在，人们仍继续饮酒，这是酗酒的一个标志，也是治疗干预的一个关键挑战。以前的大鼠研究表明，只有在长期摄入（> 8 个月）后，才会出现对酒精与正常厌恶刺激结合的持久酒精自我给药。抗厌恶的酒精摄入以前被解释为对饮酒的病理性或强迫性动机。然而，鉴于以前研究中建模强迫性酒精寻找所需的时间，人们对开发更有效和定量的抗厌恶酒精自我给药的啮齿动物模型产生了浓厚的兴趣。
近交 Wistar 大鼠接受 3 至 4 个月或大约 1.5 个月的间歇性、家庭笼、双瓶（IAA）20%酒精（v/v）或水。然后，在进行短暂的操作性训练后，通过逐步比率（PR）来量化苦味奎宁（0.1 g/l）对寻求酒精的动机的影响。在 3 至 4 个月 IAA 大鼠的另一队列中，测定了 PR 下受奎宁污染的 2%蔗糖的动机。还检查了奎宁对 IAA 大鼠和持续饮酒大鼠的笼内饮酒的影响。最后，确定了 IAA 和连续接触动物中奎宁味觉偏好的剂量反应。
使用操作性 PR 程序测量的 3 至 4 个月 IAA 后，酒精的动机不受 0.1 g/l 奎宁污染酒精的影响。相比之下，在 3 至 4 个月的 IAA 后，PR 下蔗糖的动机因 0.1 g/l 奎宁污染蔗糖而显著降低。此外，仅大约 1.5 个月 IAA 后，酒精的动机因 0.1 g/l 奎宁污染酒精而显著降低。此外，在连续接触酒精的动物中，浓度（0.01、0.03 g/l）显著减少酒精摄入的奎宁对 IAA 大鼠的笼内酒精摄入没有影响。最后，在 3 至 4 个月 IAA 或连续接触酒精后，没有观察到奎宁味觉偏好的变化。
我们开发了一种新的、技术上简单的混合操作性/IAA 模型，在该模型中，奎宁对酒精的抗动机在可实验的时间内（3 至 4 个月与 8 个月）是明显的。奎宁显著减少了 IAA 大鼠的蔗糖和水摄入量，这表明尽管奎宁具有正常的厌恶作用，IAA 大鼠继续对酒精作出反应，这可能反映了对酒精的适应不良或强迫性动机。该模型可以促进对人类病理性酒精寻求的新治疗干预措施的识别。
