Liu Y, Deitrich R A
University of Colorado Health Sciences Center, Department of Pharmacology and Alcohol Research Center, Denver 80262, USA.
Pharmacol Biochem Behav. 1998 Aug;60(4):793-801. doi: 10.1016/s0091-3057(97)00479-6.
Rats from the N/Nih heterogeneous stock have been selectively bred for high (HAS) or low (LAS) initial sensitivity to injected ethanol as measured by duration of the loss of the righting reflex. The selection for ethanol sensitivity in these lines apparently has reached a maximum. These lines are useful to elucidate the central nervous system mechanisms of the genetic differences between the lines and also provide clues to the mechanisms of ethanol's action. We have found that: 1) ethanol, etomidate, and ketamine but not propofol produce different sleep times and brain levels of the drug on awakening between these two lines; 2) only ethanol, etomidate, and ketamine produced significant differences between the HAS and LAS rats in GABA-mediated stimulation of chloride uptake into brain microsacs; 3) GABA, propofol, and etomidate decreased the Kd for flunitrazepam binding to whole-brain membranes but equally in both lines. Neither ethanol nor ketamine had an effect; 4) only GABA, ethanol, and etomidate increased the Kd for TBPS binding and only GABA decreased Bmax of TBPS binding. As with the previous selection for ethanol sensitivity in mice (short and long sleep) these lines of rats have very marked line differences in GABA-mediated events, and these are correlated with the sedative effects of ethanol. From these and previous studies we know that the major differences between selected lines of mice and rats are that the mouse lines are not differentially sensitive to halothane or pentobarbital while the rat lines are. However, the mouse lines are differentially sensitive to propofol and the rat lines are not. These data should be useful in dissecting the actions of ethanol at the GABA(A) receptor.
通过翻正反射丧失的持续时间来衡量，从N/Nih异种品系大鼠中选择性培育出了对注射乙醇具有高（HAS）或低（LAS）初始敏感性的品系。这些品系对乙醇敏感性的选择显然已达到最大值。这些品系有助于阐明品系间遗传差异的中枢神经系统机制，也为乙醇作用机制提供线索。我们发现：1）乙醇、依托咪酯和氯胺酮，但丙泊酚不会使这两个品系在睡眠时长和苏醒时大脑中的药物水平产生差异；2）只有乙醇、依托咪酯和氯胺酮在HAS和LAS大鼠之间，在GABA介导的脑微粒体氯离子摄取刺激方面产生显著差异；3）GABA、丙泊酚和依托咪酯降低了氟硝西泮与全脑细胞膜结合的解离常数（Kd），但两个品系的降低程度相同。乙醇和氯胺酮均无此作用；4）只有GABA、乙醇和依托咪酯增加了TBPS结合的Kd，只有GABA降低了TBPS结合的最大结合容量（Bmax）。与之前对小鼠乙醇敏感性的选择（短睡眠和长睡眠）一样，这些大鼠品系在GABA介导的事件中存在非常明显的品系差异，且这些差异与乙醇的镇静作用相关。从这些研究以及之前的研究中我们知道，所选小鼠和大鼠品系之间的主要差异在于，小鼠品系对氟烷或戊巴比妥无差异敏感性，而大鼠品系有。然而，小鼠品系对丙泊酚有差异敏感性，而大鼠品系没有。这些数据应有助于剖析乙醇在GABAA受体上的作用。
