Chappell Ann M, Weiner Jeff L
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 57157, USA.
Alcohol Clin Exp Res. 2008 Dec;32(12):2088-99. doi: 10.1111/j.1530-0277.2008.00797.x. Epub 2008 Sep 25.
Human studies have suggested an important relationship between ethanol sensitivity and risk of alcoholism. These studies have led some to hypothesize that a low initial sensitivity to ethanol's depressant effects and/or an elevated response to ethanol's stimulant effects may represent important risk factors associated with the development of abusive drinking behavior. Unfortunately, elucidating neurobiologic mechanisms that may underlie these relationships between ethanol sensitivity and ethanol drinking have been hampered by difficulties in modeling some of these interactions in animals. In this study, we re-examined some of these relationships in an outbred strain of rats using continuous access two-bottle choice drinking and a limited-access operant procedure that engenders pharmacologically relevant levels of ethanol intake and permits the discrete assessment of appetitive and consummatory measures of ethanol drinking behavior.
Twenty-three male Long-Evans rats were habituated to a locomotor activity box and then tested for their response to a stimulant (0.5 g/kg) and depressant (1.5 g/kg) ethanol dose. Rats were then trained to complete a lever pressing requirement to gain access to 10% ethanol for 20-minute sessions conducted 5 d/wk for 5 weeks. Appetitive behavior was assessed after 2.5 and 4.5 weeks using 20-minute extinction trials in which ethanol was not presented and lever responses were recorded. Home-cage ethanol preference was also assessed prior to and immediately following the 5-week self-administration regimen using a continuous access, two-bottle choice procedure.
A significant increase in home-cage ethanol preference was observed following the self-administration procedure, however, neither measure of ethanol preference correlated with average daily ethanol intake during the operant self-administration sessions or with initial sensitivity to ethanol's stimulant or depressant effects. Notably, a significant negative correlation was observed between sensitivity to ethanol's locomotor depressant effect and daily intake during the operant self-administration sessions. No significant relationships were noted between sensitivity to ethanol's locomotor effects and extinction responding.
The results of these studies suggest that the well-established relationship between a low level of response to ethanol and increased ethanol consumption reported in human studies can be observed in an outbred rodent strain using a limited-access operant self-administration procedure, but not with home-cage ethanol drinking.
人体研究表明乙醇敏感性与酒精中毒风险之间存在重要关联。这些研究促使一些人提出假设,即对乙醇抑制作用的初始敏感性较低和/或对乙醇刺激作用的反应增强可能是与酗酒行为发展相关的重要风险因素。不幸的是,由于在动物模型中模拟其中一些相互作用存在困难,阐明乙醇敏感性与乙醇饮用之间这些关系背后的神经生物学机制受到了阻碍。在本研究中,我们使用连续获取两瓶选择饮水法和有限获取操作性程序,对远交系大鼠中的其中一些关系进行了重新研究,该操作性程序可产生药理学上相关水平的乙醇摄入量,并允许对乙醇饮用行为的食欲和 consummatory 测量进行离散评估。
23 只雄性 Long-Evans 大鼠适应运动活动箱,然后测试它们对刺激剂量(0.5 g/kg)和抑制剂量(1.5 g/kg)乙醇的反应。然后训练大鼠完成杠杆按压要求,以在每周 5 天、为期 5 周的 20 分钟时段内获取 10%的乙醇。在 2.5 周和 4.5 周后,使用 20 分钟的消退试验评估食欲行为,在该试验中不提供乙醇并记录杠杆反应。在 5 周自我给药方案之前和之后,还使用连续获取两瓶选择程序评估笼内乙醇偏好。
在自我给药程序后,观察到笼内乙醇偏好显著增加,然而,乙醇偏好的两种测量方法均与操作性自我给药时段期间的平均每日乙醇摄入量或与对乙醇刺激或抑制作用 的初始敏感性无关。值得注意的是,在操作性自我给药时段期间,对乙醇运动抑制作用的敏感性与每日摄入量之间观察到显著负相关。在对乙醇运动作用的敏感性与消退反应之间未观察到显著关系。
这些研究结果表明,使用有限获取操作性自我给药程序,在远交啮齿动物品系中可以观察到人体研究中报道的对乙醇反应水平低与乙醇消耗量增加之间的既定关系,但在笼内乙醇饮用中未观察到这种关系。