Palmer Abraham A, Phillips Tamara J
Portland Alcohol Research Center and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon 97239, USA.
Alcohol Clin Exp Res. 2002 Sep;26(9):1322-9. doi: 10.1097/01.ALC.0000029583.65878.0E.
Ethanol sensitivity may be a predictor of genetic predisposition to ethanol abuse. To examine ethanol sensitivity in rodents, two lines of mice were bred in replicate for high (FAST-1 and -2) and low (SLOW-1 and -2) locomotor stimulant responses to ethanol. After large differences between the lines developed and further response to selection seemed to have arrested, reverse selection was initiated by breeding the slowest FAST mice with each other and the fastest SLOW mice with each other. The reverse-selected lines, named r-FAST and r-SLOW, were virtually equally sensitive to the stimulant effects of the selection dose of ethanol after 16 generations of reverse selection.
These experiments used this unique genetic model to examine two responses, putatively genetically correlated with sensitivity to ethanol stimulation: handling-induced convulsions during chronic ethanol withdrawal, and ethanol-induced hypothermia. Ethanol clearance, for which a small difference was previously found between the FAST and SLOW lines, was also examined.
Handling-induced convulsions during chronic ethanol withdrawal were significantly greater in both FAST lines compared with both SLOW lines. Reverse selection eliminated the difference between the replicate 1 lines but did not alter the difference between the replicate 2 lines. Ethanol-induced hypothermia was greater in both SLOW lines compared with the FAST lines. This difference was significantly reduced by reverse selection in r-SLOW mice only. Ethanol clearance rates were similar among all lines and replicates.
These data demonstrate the usefulness of reverse-selected lines for examining putatively genetically correlated traits. Changes in the correlated traits demonstrated the existence of persistent trait-relevant genetic heterogeneity and some genetic overlap between the correlated traits and the selection trait. Absence of a change after reverse selection suggests that trait-relevant genetic heterogeneity was eliminated by forward selection or, alternatively, that the trait was not influenced by genes associated with successful reverse selection.
乙醇敏感性可能是乙醇滥用遗传易感性的一个预测指标。为了研究啮齿动物的乙醇敏感性，培育了两个品系的小鼠，分别对乙醇的运动刺激反应进行高（FAST - 1和 - 2）和低（SLOW - 1和 - 2）重复选育。当品系间出现较大差异且对选择的进一步反应似乎停止后，通过将最慢的FAST小鼠相互交配以及最快的SLOW小鼠相互交配启动反向选择。经过16代反向选择后，名为r - FAST和r - SLOW的反向选择品系对选择剂量乙醇的刺激作用几乎同样敏感。
这些实验使用这个独特的遗传模型来研究两个反应，推测这两个反应与乙醇刺激敏感性存在遗传相关性：慢性乙醇戒断期间处理诱导的惊厥以及乙醇诱导的体温过低。还研究了乙醇清除率，此前在FAST和SLOW品系之间发现了微小差异。
与两个SLOW品系相比，两个FAST品系在慢性乙醇戒断期间处理诱导的惊厥明显更严重。反向选择消除了重复1品系之间的差异，但未改变重复2品系之间的差异。与FAST品系相比，两个SLOW品系中乙醇诱导的体温过低情况更严重。仅在r - SLOW小鼠中通过反向选择显著降低了这种差异。所有品系和重复之间的乙醇清除率相似。
这些数据证明了反向选择品系在研究推测的遗传相关性状方面的有用性。相关性状的变化表明存在持续的性状相关遗传异质性以及相关性状与选择性状之间的一些遗传重叠。反向选择后没有变化表明性状相关遗传异质性已通过正向选择消除，或者该性状不受与成功反向选择相关的基因影响。
