Smolen A, Marks M J, DeFries J C, Henderson N D
Institute for Behavioral Genetics, University of Colorado, Boulder 80309-0447.
Pharmacol Biochem Behav. 1994 Nov;49(3):531-40. doi: 10.1016/0091-3057(94)90065-5.
Four hundred seventeen heterogeneous stock mice were tested for their relative sensitivity to a low dose of nicotine (0.75 mg/kg) using activity in an automated Y-maze and body temperature as response measures. A wide spectrum of individual responsiveness to nicotine, ranging from complete suppression of activity to stimulation above baseline activity, was found. Replicate measures taken 1 week later on the same animals showed the responses to nicotine to be reliable and reproducible. Activity levels and body temperatures following nicotine administration were highly correlated (r = 0.60, df = 415). From analysis of between-litter proportions of variance, the heritability of nicotine-influenced activity was estimated to be 0.12, indicating that selective breeding for differential responsiveness to nicotine would be possible. The 10 most activated and 10 most depressed male and female mice were chosen as breeders for replicate nicotine activated (NA) and nicotine depressed (ND) lines, respectively. The selection criterion was nicotine-induced activity corrected for baseline activity using regression residuals. After six generations of selective breeding a good response to selection was obtained, although the response was better for the ND than for the NA lines. Realized heritability for responsiveness to nicotine calculated from the six selected generations was found to be 0.20, or slightly greater than that estimated from the foundation population. There were no significant differences in response to selection between the replicate NA or ND lines. Nicotine-induced body temperature was measured as a correlated response to selection, and was found to remain highly correlated with nicotine-induced locomotor activity. The response was more robust for the ND lines than it was for the NA lines. In contrast to the large differences between the ND and NA lines in locomotor activity and body temperatures following nicotine administration, mean baseline activities and body temperatures remained nearly identical throughout. This indicates that selection acted specifically on nicotine-induced responses, and not on baseline measurements, as predicted for response to a selection criterion based on regression residuals.
使用自动Y迷宫中的活动和体温作为反应指标，对417只异质系小鼠进行了低剂量尼古丁（0.75mg/kg）相对敏感性测试。发现小鼠对尼古丁的个体反应范围很广，从活动完全受抑制到高于基线活动水平的兴奋状态。在同一批动物1周后进行的重复测量显示，对尼古丁的反应是可靠且可重复的。给予尼古丁后的活动水平和体温高度相关（r = 0.60，自由度 = 415）。通过分析窝间方差比例，估计尼古丁影响活动的遗传力为0.12，这表明针对尼古丁反应差异进行选择性育种是可行的。分别选择10只最活跃和10只最不活跃的雄性和雌性小鼠作为种鼠，用于培育重复的尼古丁兴奋（NA）系和尼古丁抑制（ND）系。选择标准是使用回归残差对基线活动进行校正后的尼古丁诱导活动。经过六代选择性育种，获得了对选择的良好反应，尽管ND系的反应比NA系更好。从六个选定世代计算得出的对尼古丁反应的实际遗传力为0.20，略高于基础种群的估计值。重复的NA或ND系之间在选择反应上没有显著差异。测量尼古丁诱导的体温作为选择的相关反应，发现其与尼古丁诱导的运动活动仍高度相关。ND系的反应比NA系更强健。与尼古丁给药后ND系和NA系在运动活动和体温上的巨大差异相反，整个过程中平均基线活动和体温几乎保持相同。这表明选择特异性地作用于尼古丁诱导的反应，而不是基线测量，正如基于回归残差的选择标准所预测的那样。
