DIAZEPAM DISCRIMINATION IN GABA SUBUNIT KNOCKOUT MICE

GABA 亚基敲除小鼠中地西泮的歧视

• 批准号: 6231440
• 负责人: KEITH L SHELTON
• 金额: $ 0.72万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 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 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6231440
• 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/抗焦虑药的误用和滥用是我们社会中的严重问题。的 这些药物中最常见的是苯二氮卓类和巴比妥类药物， GABA-A受体功能的变构调节剂。GABA-A受体 来自至少五个亚基家族（α 1-6， β 1-4、γ 1-3、δ和γ）。体外研究表明 GABA-A受体亚基组成对GABA配体的作用至关重要。 重组GABA-A受体中δ亚基的存在赋予了 对GABA敏感性增加，对苯二氮卓类不敏感， 神经类固醇最近，缺乏功能性GABA-A δ亚单位的小鼠， 被创造出来。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 亚基组成的多种补偿性变化可能会发生， δ亚基缺失此应用程序将使用药物歧视 受体介导的主观辨别刺激的研究范式 地西泮在δ亚基敲除小鼠中的作用。辨别刺激 药物的作用是特异性受体相互作用的函数， 被认为与滥用责任有关。第一个具体目标是 建议在δ基因敲除小鼠中建立地西泮辨别， 野生型对照。据推测，这两种品系的小鼠将 成功地获得歧视，但将在所需的时间不同， 达到标准性能。第二个主要目标是确定三角洲是否 亚基在地西泮的辨别性刺激效应中起作用， 其他GABA-A调节剂。根据数据显示， δ基因敲除小鼠，我们相信每个品系都会表现出独特的 GABA-A调节剂对地西泮取代概况。这些数据将提供 一个重要的特征的区别性刺激效果的 在δ亚基敲除中使用地西泮，这将是第一个研究 在任何敲除小鼠中药物的区别性刺激效应。此外，本发明还 这项研究的结果可能有助于阐明特定的 GABA受体的亚基改变转化为细胞内 镇静/抗焦虑药物的行为影响。