Linsenbardt David N, Boehm Stephen L
Psychobiology of Addictions, Department of Psychology and Indiana Alcohol Research Center, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202, USA,
Psychopharmacology (Berl). 2013 Nov;230(2):267-78. doi: 10.1007/s00213-013-3151-4. Epub 2013 Jun 4.
Sensitization to the locomotor stimulant effects of alcohol (ethanol) is thought to be a heritable risk factor for the development of alcoholism that reflects progressive increases in the positive motivational effects of this substance. However, very little is known about the degree to which genes influence this complex behavioral phenomenon.
The primary goal of this work was to determine the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection.
Genetically heterogeneous C57BL/6J (B6) × DBA/2J (D2) F2 mice were generated from B6D2F1 progenitors, phenotyped for the expression of locomotor sensitization, and bred for high (HLS) and low (LLS) expression of this behavior. Selective breeding was conducted in two independently generated replicate sets to increase the confidence of our heritability estimates and for future correlated trait analyses.
Large and significant differences in locomotor sensitization between HLS and LLS lines were evident by the fourth generation. Twenty-two percent of the observed line difference(s) were attributable to genes (h² = .22). Interestingly, locomotor activity in the absence of ethanol was genetically correlated with ethanol sensitization; high activity was associated with high sensitization.
That changes in ethanol sensitivity following repeated exposures are genetically regulated highlights the relevance of studies aimed at determining how genes regulate susceptibility to ethanol-induced behavioral and neural adaptations. As alcohol use and abuse disorders develop following many repeated alcohol exposures, these data emphasize the need for future studies determining the genetic basis by which changes in response to alcohol occur.
对酒精（乙醇）的运动刺激作用产生敏化被认为是酒精成瘾发展的一种可遗传风险因素，这反映了该物质积极动机效应的逐渐增加。然而，关于基因在多大程度上影响这种复杂的行为现象，人们知之甚少。
这项工作的主要目标是通过短期行为选择来确定小鼠中乙醇诱导的运动敏化的遗传性。
从B6D2F1祖代产生基因异质的C57BL/6J（B6）×DBA/2J（D2）F2小鼠，对运动敏化的表达进行表型分析，并针对这种行为的高（HLS）和低（LLS）表达进行选育。在两个独立产生的重复组中进行选择性育种，以提高我们遗传力估计的可信度，并用于未来的相关性状分析。
到第四代时，HLS和LLS品系之间的运动敏化存在巨大且显著的差异。观察到的品系差异中有22%可归因于基因（h² = 0.22）。有趣的是，在没有乙醇的情况下的运动活动与乙醇敏化在基因上相关；高活动与高敏化相关。
反复接触后乙醇敏感性的变化受到基因调控，这突出了旨在确定基因如何调节对乙醇诱导的行为和神经适应易感性的研究的相关性。由于酒精使用和滥用障碍是在多次反复接触酒精后发展而来的，这些数据强调了未来研究确定酒精反应变化的遗传基础的必要性。
