Radcliffe Richard A, Floyd Kirsten L, Drahnak Joseph A, Deitrich Richard A
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Alcohol Clin Exp Res. 2005 Sep;29(9):1580-9. doi: 10.1097/01.alc.0000179208.05882.1f.
The Inbred Long- and Short-Sleep mice (ILS and ISS) and the Inbred High- and Low-Alcohol-Sensitive rats (IHAS and ILAS) were selectively bred for differential alcohol sensitivity with use of the duration of loss-of-righting-reflex test (LORR), with the IHAS and ILS animals being much more sensitive than the ILAS and ISS animals, respectively. The current study was undertaken to determine whether acute sensitivity in these strains is genetically correlated to a rapid tolerance to alcohol, a form of tolerance that is evident 24 hr after a single alcohol dose.
Separate groups of animals were administered a single pretreatment dose of alcohol (0-6 g/kg for the mice; 0-4 g/kg for the rats). Alcohol sensitivity was tested 24 hr later with the LORR test, and blood ethanol concentration was tested at regain of righting (BECRR). Alcohol-induced hypothermia also was determined in the mice. Independently derived replicate rat strains were used for all experiments (IHAS1, ILAS1; IHAS2, ILAS2); no such replicates exist for the ILS and ISS strains.
Alcohol pretreatment caused a dose-dependent decrease in LORR duration accompanied by an increase in BECRR in the ILS strain, but LORR increased in the ISS strain with no effect on BECRR. Both strains became hypothermic during the LORR test on day two, but the only significant effect of alcohol pretreatment was in the ISS strain, in which alcohol-induced hypothermia was enhanced. Alcohol pretreatment caused a significant dose-dependent decrease in LORR duration accompanied by an increase in BECRR in the IHAS1 but not in the IHAS2 strain. In contrast, ILAS1 and ILAS2 strains both showed a significant increase in LORR duration and also a significant increase in BECRR.
Alcohol pretreatment caused a dose-dependent decrease in LORR duration and an increase in BECRR in the IHAS1 and ILS strain, suggesting the development of functional rapid tolerance. In contrast, LORR duration increased in the ILAS1, ILAS2, and ISS groups, but BECRR either increased (ILAS1, ILAS2) or did not change (ISS). These observations suggest that central nervous system sensitivity was decreased in the ILAS1 and ILAS2 groups (i.e., rapid functional tolerance) or unchanged in the ISS strain, but that some pharmacokinetic property also was altered in these strains. Overall, the results do not support a genetic relation between alcohol sensitivity and the development of rapid tolerance.
近交系长睡眠和短睡眠小鼠（ILS和ISS）以及近交系高酒精敏感性和低酒精敏感性大鼠（IHAS和ILAS）是通过翻正反射消失试验（LORR）的持续时间来选择性培育以区分酒精敏感性的，其中IHAS和ILS动物分别比ILAS和ISS动物对酒精敏感得多。本研究旨在确定这些品系中的急性敏感性是否与对酒精的快速耐受性存在遗传相关性，快速耐受性是单次给予酒精剂量24小时后明显出现的一种耐受性形式。
将动物分为不同组，分别给予单次预处理剂量的酒精（小鼠为0 - 6 g/kg；大鼠为0 - 4 g/kg）。24小时后用LORR试验测试酒精敏感性，并在恢复翻正反射时检测血乙醇浓度（BECRR）。还在小鼠中测定了酒精诱导的体温过低情况。所有实验均使用独立衍生的重复大鼠品系（IHAS1、ILAS1；IHAS2、ILAS2）；ILS和ISS品系不存在这样的重复品系。
酒精预处理导致ILS品系的LORR持续时间呈剂量依赖性缩短，同时BECRR升高，但ISS品系的LORR延长，而对BECRR无影响。在第二天的LORR试验期间，两个品系均出现体温过低，但酒精预处理的唯一显著影响出现在ISS品系中，其中酒精诱导的体温过低情况增强。酒精预处理导致IHAS1品系的LORR持续时间显著呈剂量依赖性缩短，同时BECRR升高，但在IHAS2品系中未出现这种情况。相比之下，ILAS1和ILAS2品系的LORR持续时间均显著增加，且BECRR也显著升高。
酒精预处理导致IHAS1和ILS品系的LORR持续时间呈剂量依赖性缩短，BECRR升高，提示功能性快速耐受性的形成。相比之下，ILAS1、ILAS2和ISS组的LORR持续时间增加，但BECRR要么升高（ILAS1、ILAS2），要么未改变（ISS）。这些观察结果表明，ILAS1和ILAS2组的中枢神经系统敏感性降低（即快速功能性耐受性），或ISS品系未改变，但这些品系的一些药代动力学特性也发生了改变。总体而言，结果不支持酒精敏感性与快速耐受性形成之间存在遗传关系。
