Erwin V G, Deitrich R A
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, USA.
J Pharmacol Exp Ther. 1996 Dec;279(3):1310-7.
Rapid adaptation to central nervous system inhibitory effects of ethanol is observed in animals and humans and this acute functional tolerance (AFT) is influenced by genotype in rodents. Studies have been conducted to identify neurochemical processes influencing AFT to ethanol, but little is known regarding genetic regulation of AFT or genetic influences on processes that mediate acquisition of AFT. Our study was designed to develop, by selective breeding, lines of mice that differ in acquisition of AFT to ethanol; such mouse lines will be valuable in identifying the neuroadaptive processes mediating AFT. AFT is defined as the difference in blood ethanol concentration (BEC) at regaining balance on a stationary dowel rod after two consecutive doses of ethanol, 1.75 followed by 2.0 g/kg. Starting with a genetically heterogeneous foundation stock (HS/lbg), seven generations of selective breeding has been completed for high (HAFT1), low (LAFT1), and control lines and four generations have been completed for the replicate HAFT2 and LAFT2 lines. The lines do not differ in initial sensitivity to ethanol; however, the means for AFT scores differ by 2.3- and 4.3-fold for females and males, respectively (106.5 vs. 46.5 mg ethanol/dl blood) for females and 106.2 vs. 24.8 mg/dl for males). Frequency distributions for HAFT1 and LAFT1 show only modest overlap in AFT scores. The lines differ in rates of acquisition of AFT, but not in rates of ethanol clearance. Heritabilities were 0.04 and 0.26 for HAFT1 and LAFT1 lines, respectively, indicating that the selection was asymmetrical. Evidence is provided indicating that practice during intoxication has little effect on acquisition of AFT in HAFT1 and LAFT1 lines.
在动物和人类中均观察到对乙醇中枢神经系统抑制作用的快速适应，这种急性功能耐受性（AFT）在啮齿动物中受基因型影响。已开展研究以确定影响对乙醇AFT的神经化学过程，但对于AFT的遗传调控或对介导AFT获得过程的遗传影响知之甚少。我们的研究旨在通过选择性育种培育出对乙醇AFT获得存在差异的小鼠品系；这样的小鼠品系对于识别介导AFT的神经适应性过程将具有重要价值。AFT定义为在连续两次给予乙醇剂量（先1.75 g/kg，后2.0 g/kg）后，在固定木钉上恢复平衡时的血液乙醇浓度（BEC）差异。从遗传异质的基础种群（HS/lbg）开始，已完成了高（HAFT1）、低（LAFT1）和对照品系的七代选择性育种，以及重复的HAFT2和LAFT2品系的四代选择性育种。这些品系对乙醇的初始敏感性并无差异；然而，雌性和雄性的AFT评分均值分别相差2.3倍和4.3倍（雌性为106.5对vs. 46.5 mg乙醇/dl血液，雄性为106.2对vs. 24.8 mg/dl）。HAFT1和LAFT1的频率分布显示AFT评分仅有适度重叠。这些品系在AFT获得速率上存在差异，但在乙醇清除速率上无差异。HAFT1和LAFT1品系的遗传力分别为0.04和0.26，表明选择是不对称的。有证据表明，中毒期间的训练对HAFT1和LAFT1品系的AFT获得影响不大。
