DIAZEPAM DISCRIMINATION IN GABA SUBUNIT KNOCKOUT MICE

描述：(申请人摘要) 镇静剂/抗焦虑药的滥用和滥用是我们社会的严重问题。这个 这些药物中最常见的苯二氮卓类和巴比妥类药物是阳性的。 GABA-A受体功能的变构调节剂。GABA-A受体是 来自至少五个亚基家族(阿尔法1-6， 贝塔1-4、伽马1-3、三角洲和埃西隆)。体外研究表明， GABA-A受体亚单位的组成对GABA配体的作用至关重要。 重组GABA-A受体中的Delta亚单位的存在 对GABA的敏感性增加，对苯二氮卓类药物不敏感 神经类固醇。最近，缺乏功能性GABA-A增量亚单位的小鼠 已经被创建了。在这些动物中，神经类固醇诱导的睡眠时间减少 与基于重组受体的预测形成直接对比。这表明 其结果是亚基组成可能发生多重补偿性变化 德尔塔亚基缺失。这个应用程序将使用毒品歧视 受体介导的主观辨别性刺激的研究范式 安定对Delta亚单位基因敲除小鼠的影响。歧视性刺激 药物的作用是特定受体相互作用的函数，并且 据信与滥用责任有关。这样做的第一个具体目标是 建议在Delta基因敲除小鼠和 野生型对照。据推测，这两种品系的小鼠都会 成功获得歧视，但所需时间不同 达到绩效标准。第二个主要目标是确定三角洲是否 亚基在安定和安非他明的区分性刺激效应中起作用 其他GABA-A调节剂。基于显示神经类固醇效应改变的数据 Delta基因敲除小鼠，我们相信每个品系都会表现出独特的 GABA-A调节剂对安定的替代谱。这些数据将提供 的歧视性刺激效应的一个重要特征 安定在Delta亚基敲除中的作用，这将是对 一种药物在任何基因敲除小鼠中的区别刺激效应。另外， 这项研究的结果可能有助于阐明特定情况下的变化 GABA受体亚单位的改变转化为 镇静/抗焦虑药物的行为影响。

DESCRIPTION: (Applicant's Abstract) Sedative/anxiolytic misuse and abuse are serious problems in our society. The most common of these drugs, benzodiazepine and barbiturates, are positive allosteric modulators of GABA-A receptor function. GABA-A receptors are heteropentameric assemblies from at least five subunit families (alpha 1-6, beta 1-4, gamma 1-3, delta and epsilon). In vitro studies have shown that GABA-A receptor subunit composition is critical to the actions of GABA ligands. The presence of a delta subunit in recombinant GABA-A receptors confers increased sensitivity to GABA and insensitivity to benzodiazepines and neurosteroids. Recently, mice lacking a functional GABA-A delta subunit have been created. Neurosteroid-induced sleep time is decreased in these animals, in direct contrast to predictions based on recombinant receptors. This suggests that multiple compensatory changes in subunit composition may occur as a result of delta subunit deletion. This application will use the drug discrimination paradigm to examine the receptor-mediated subjective discriminative stimulus effects of diazepam in delta subunit knockout mice. The discriminative stimulus effects of a drug are a function of specific receptor interactions and are believed to be related to abuse liability. The first specific aim of this proposal is to establish a diazepam discrimination in delta knockout mice and wild-type controls. It is hypothesized that both strains of mice will successfully acquire the discrimination but will differ in the time required to reach criteria performance. The second major aim is to determine if the delta subunit plays a role in the discriminative stimulus effects of diazepam and other GABA-A modulators. Based on data showing altered neurosteroid effects in delta knockout mice, we believe that each strain will exhibit a unique substitution profile of GABA-A modulators for diazepam. These data will provide an important characterization of the discriminative stimulus effects of diazepam in delta subunit knockouts and would be the first study of the discriminative stimulus effects of a drug in any knockout mouse. Additionally, the results from this study may help to elucidate how changes in specific subunit alterations of the GABA receptor translate into changes in the behavioral effects of sedative/anxiolytic drugs.