Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
PLoS One. 2012;7(8):e44234. doi: 10.1371/journal.pone.0044234. Epub 2012 Aug 28.
Adult cigarette smokers usually become dependent on cigarettes during adolescence. Despite recent advances in addiction genetics, little data delineates the genetic factors that account for the vulnerability of humans to smoke tobacco. We studied the operant nicotine self-administration (SA) behavior of six inbred strains of adolescent male rats (Fisher 344, Brown Norway, Dark Agouti, Spontaneous Hypertensive Rat, Wistar Kyoto and Lewis) and six selected F1 hybrids. All rats were trained to press a lever to obtain food starting on postnatal day (PN) 32, and then nicotine (0.03 mg/kg/infusion, i.v.) reinforcement was made available on PN41-42 (10 consecutive daily 2 h sessions). Of the 12 isogenic strains, Fisher rats self-administered the fewest nicotine infusions (1.45 ± 0.36/d) during the last 3 d, while Lewis rats took the most nicotine (13.0 ± 1.4/d). These strains sorted into high, intermediate and low self-administration groups in 2, 2, and 8 strains, respectively. The influence of heredity on nicotine SA (0.64) is similar to that reported for humans. Therefore, this panel of isogenic rat strains effectively models the overall impact of genetics on the vulnerability to acquire nicotine-reinforced behavior during adolescence. Separate groups of rats responded for food starting on PN41. The correlation between nicotine and food reward was not significant. Hence, the genetic control of the motivation to obtain nicotine is distinctly different from food reward, indicating the specificity of the underlying genetic mechanisms. Lastly, the behavior of F1 hybrids was not predicted from the additive behavior of the parental strains, indicating the impact of significant gene-gene interactions on the susceptibility to nicotine reward. Taken together, the behavioral characteristics of this model indicate its strong potential to identify specific genes mediating the human vulnerability to smoke cigarettes.
成年烟民通常在青少年时期就对香烟产生依赖。尽管成瘾遗传学最近取得了进展，但很少有数据能描绘出导致人类易吸烟的遗传因素。我们研究了 6 种近交系雄性青少年大鼠（Fisher 344、Brown Norway、Dark Agouti、Spontaneous Hypertensive Rat、Wistar Kyoto 和 Lewis）和 6 种选定的 F1 杂种的操作性尼古丁自我给药（SA）行为。所有大鼠均在出生后第 32 天（PN）开始接受按压杠杆获取食物的训练，然后在 PN41-42 天（连续 10 天每天 2 小时）给予尼古丁（0.03mg/kg/ 注射，iv）强化。在这 12 种同基因品系中，Fisher 大鼠在最后 3 天内自我给予的尼古丁注射次数最少（1.45±0.36/天），而 Lewis 大鼠给予的尼古丁最多（13.0±1.4/天）。这些品系分别分为高、中、低自我给药组，分别有 2、2 和 8 个品系。遗传对尼古丁 SA（0.64）的影响与人类报告的相似。因此，这组同基因大鼠品系有效地模拟了遗传对青少年时期易获得尼古丁强化行为的整体影响。另一组大鼠从 PN41 开始按压杠杆获取食物。尼古丁和食物奖励之间的相关性不显著。因此，获得尼古丁的动机的遗传控制与食物奖励明显不同，表明潜在遗传机制的特异性。最后，F1 杂种的行为不能从亲本品系的加性行为中预测，表明基因-基因相互作用对尼古丁奖励易感性的影响。总之，该模型的行为特征表明其具有很强的潜力，可以确定介导人类吸烟易感性的特定基因。
