DIAZEPAM DISCRIMINATION IN GABA SUBUNIT KNOCKOUT MICE

GABA 亚基敲除小鼠中地西泮的歧视

• 批准号: 6430451
• 负责人: KEITH L SHELTON
• 金额: $ 6.53万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6430451
• 关键词: GABA receptor; behavioral /social science research tag; biological models; diazepam; gamma aminobutyrate; genetically modified animals; laboratory mouse; psychopharmacology; substance abuse related behavior

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.

描述：（申请人摘要） 镇静剂/抗焦虑剂的误用和滥用是我们社会的严重问题。这 这些药物中最常见的是苯二氮卓类药物和巴比妥类药物，呈阳性 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（α 1-6， beta 1-4、gamma 1-3、delta 和 epsilon）。体外研究表明 GABA-A 受体亚基组成对于 GABA 配体的作用至关重要。 重组 GABA-A 受体中 δ 亚基的存在赋予 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 δ 亚基的小鼠 被创建。神经类固醇诱导的这些动物的睡眠时间减少 与基于重组受体的预测形成直接对比。这表明 结果可能会发生亚基组成的多重补偿性变化 δ亚基缺失。该应用程序将使用药物歧视 检查受体介导的主观辨别刺激的范式 地西泮对 Delta 亚基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，并且是 据信与滥用责任有关。本次活动的第一个具体目标 提案是在 Delta 基因敲除小鼠中建立地西泮歧视， 野生型对照。据推测，两种品系的小鼠都会 成功获得歧视，但所需时间会有所不同 达到标准性能。第二个主要目标是确定三角洲是否 亚基在地西泮和地西泮的辨别刺激作用中发挥作用 其他 GABA-A 调节剂。基于显示神经类固醇作用改变的数据 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 调节剂对地西泮的替代概况。这些数据将提供 区分性刺激效应的一个重要特征 地西泮在 Delta 亚基敲除中的作用，将是第一个研究 药物对任何基因敲除小鼠的区别性刺激作用。此外， 这项研究的结果可能有助于阐明具体的变化是如何发生的 GABA 受体亚基的改变转化为 镇静/抗焦虑药物的行为影响。