Behavioral characterization of alcohol-tolerant and alcohol-nontolerant rat lines and an F2 generation
Behavioral characterization of alcohol-tolerant and alcohol-nontolerant rat lines and an F2 generation
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DOI：
10.1023/b:bege.0000023650.32243.39
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发表时间：
2004-07-01
影响因子：
2.6
通讯作者：
Deitrich, RA
中科院分区：
文献类型：
--
作者：
Radcliffe, RA;Hoffmann, SE;Deitrich, RA
酒精耐受（AT）和酒精不耐受（ANT）大鼠，在芬兰ALKO的斜面上选择性地培育用于乙醇诱导的共济失调，于1998年转移到科罗拉多大学。在科罗拉多州对60代动物进行了选择表型测试。第一周，腹腔注射2 g/kg 15% w/v乙醇30分钟后，在斜面上测量共济失调。科罗拉多大学的AT系和ANT系在乙醇诱导的共济失调方面的差异与芬兰的原始系相似。在第2周，分别于5和30分钟在斜面上测量共济失调，并以恢复原始滑动角度的时间测量耐受性。AT大鼠对斜面2 g/kg乙醇迅速产生耐受；ANT大鼠的耐受性发展明显较慢。在第三周，给药3.5 g/kg后，对动物进行翻正反射丧失时间（LORR）和翻正反射恢复时血液乙醇浓度（BECRRR）的检测。AT组大鼠的BECRRR显著高于ANT组大鼠，但LORR无显著差异。对先前未治疗的大鼠进行的单独实验表明，这两种系的幼年动物在BECRRR或LORR方面没有差异。AT和ANT大鼠的基因型突变发生在GABA(A)受体的α 6亚基基因中，这是一种已知会影响苯二氮卓类药物反应的自然突变。所有测试的ANT动物都携带突变等位基因，而一些AT家族携带突变，其他则是野生型。在被测试的任何表型中，AT大鼠的突变都没有影响。经几代兄弟姐妹交配，经基因分型测定，AT系和ANT系90%以上为近交系。选择1个AT（野生型）系和1个ANT（突变型）系，选育了1200只动物的F-2杂交代。连续三周对它们的乙醇敏感性和耐受性进行表型分析。测试顺序对某些表型有适度的影响：与第1周或第2周相比，在第三周进行测试时，BECRRR增加，30分钟敏感性增加，急性耐受性增加。在5分钟和30分钟的耐受性和敏感性之间，以及LORR和BECRRR之间存在统计学上显著的相关性。其他表型之间较小的（或不存在）显著相关性表明它们很可能是由不同的基因组控制的。
The Alcohol Tolerant (AT) and Alcohol Nontolerant (ANT) rats, selectively bred for ethanol-induced ataxia on the inclined plane at ALKO in Finland, were moved to the University of Colorado in 1998. The selection phenotype was tested on generation 60 animals in Colorado. In week one, ataxia was measured on the inclined plane 30 minutes after an intraperitoneal dose of 2 g/kg 15% w/v ethanol. Differences in ethanol-induced ataxia between the AT and ANT lines at the University of Colorado were similar to those in the original lines in Finland. In week two, ataxia was measured on the inclined plane at 5 and 30 minutes, and tolerance was measured as the time to regain the original angle of sliding. The AT rats rapidly developed tolerance to 2 g/kg ethanol on the inclined plane; tolerance development was significantly slower in the ANT rats. In week three, the animals were tested for the duration of loss of righting reflex (LORR) and blood ethanol concentration at regain of the righting reflex (BECRRR) following a dose of 3.5 g/kg. The AT rats had a significantly higher BECRRR than did the ANT rats, but did not differ in LORR. A separate experiment with previously untreated rats demonstrated that naive animals of the two lines did not differ in BECRRR or LORR. AT and ANT rats were genotyped for the mutation that occurs in the gene for the alpha6 subunit of the GABA(A) receptor, a natural mutation that is known to affect benzodiazepine responses. All ANT animals tested carried the mutant allele, whereas some AT families carried the mutation and others were wild type. There was no effect of the mutation in AT rats for any of the phenotypes that were tested. After several generations of brother - sister mating, the AT and ANT lines were more than 90% inbred as determined by genotyping. One AT (wild-type) line and one ANT ( mutant) line were selected for breeding an F-2 intercross generation of 1200 animals. They were phenotyped for sensitivity and tolerance to ethanol on each of three consecutive weeks. Order of testing had a modest effect on some of the phenotypes: when tested during the third week as compared to weeks one or two, BECRRR was increased, 30-minute sensitivity was increased, and development of acute tolerance was increased. Statistically significant correlations were found between tolerance and sensitivity at both 5 and 30 minutes, and between LORR and BECRRR. The smaller ( or absence of) significant correlations between others of the phenotypes indicate(s) that they are most likely controlled by different sets of genes.