Gallaher E J, Hollister L E, Gionet S E, Crabbe J C
Psychopharmacology (Berl). 1987;93(1):25-30. doi: 10.1007/BF02439582.
Selective breeding techniques were used to alter allelic frequencies responsible for diazepam sensitivity and resistance. We used the rotarod test to determine the duration of diazepam-induced neurologic deficit in genetically heterogeneous mice. Males were more sensitive than females in the initial population. We then selectively bred for diazepam resistance and sensitivity. A significant difference between the lines was apparent in both sexes after two generations, and divergence has continued over seven generations. Brain benzodiazepine assays indicated that absorption and distribution of diazepam do not differ in the two lines. Differences in brain benzodiazepine concentrations at recovery from ataxia indicated that the two lines differ in central nervous system sensitivity. We found diazepam-induced rotarod impairment to be blocked in a dose-dependent manner by the specific benzodiazepine antagonist Ro 15-1788, indicating that this effect is mediated through BZ receptors. A dose-response curve obtained from generations 6 and 7 indicates a 9- to 14-fold difference in dose required to obtain similar effects in the two lines. These mice are expected to be useful experimental subjects in studies of benzodiazepine mechanisms.
采用选择性育种技术改变负责地西泮敏感性和抗性的等位基因频率。我们使用转棒试验来确定地西泮诱导的基因异质性小鼠神经功能缺损的持续时间。在初始群体中，雄性比雌性更敏感。然后我们选择性地培育出对地西泮有抗性和敏感性的品系。经过两代后，两个品系在两性中均出现了显著差异，并且这种差异在七代中持续存在。脑苯二氮䓬测定表明，两个品系中地西泮的吸收和分布没有差异。从共济失调恢复时脑苯二氮䓬浓度的差异表明，两个品系在中枢神经系统敏感性方面存在差异。我们发现，特异性苯二氮䓬拮抗剂Ro 15 - 1788以剂量依赖性方式阻断地西泮诱导的转棒损伤，这表明这种效应是通过BZ受体介导的。从第6代和第7代获得的剂量 - 反应曲线表明，在两个品系中获得相似效应所需的剂量相差9至14倍。这些小鼠有望成为苯二氮䓬作用机制研究中有用的实验对象。
