SIGNALING PATHWAY FOR BENZODIAZEPINE INDUCED BEHAVIORS

苯二氮卓类药物诱发行为的信号通路

• 批准号: 2013564
• 负责人: RAYMOND MARK QUOCK
• 金额: $ 9.25万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-15 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2013564
• 关键词: GABA receptor; arginine; benzodiazepine receptor; benzodiazepines; biological signal transduction; cyclic GMP; free radical scavengers; guanylate cyclase; laboratory mouse; microinjections; nitric oxide; nitric oxide synthase; nitrous oxide; phosphodiesterase inhibitors; phosphodiesterases; protein kinase A; psychopharmacology

DESCRIPTION: (Applicant's Abstract) Benzodiazepines are among the most widely prescribed medications in the world, While benzodazepines are both clinically efficacious and safe, there are nonetheless concerns about whether inappropriate or over prescription of these drugs contributes to abuse and dependence. The site(s) and mechanism of behavioral actions of benzodiazepines in the central nervous system (CNS) remain uncertain. The proposed research is designed to test a working hypothesis that behaviors initiated by drug action at the benzodiazepine/y aminobutyric acidA (GABAA) receptor complex are mediated by a nitric oxide (NO)/cyclic GMP (cGMP)/protein kinase G (PKG) signaling pathway, i.e., stimulation of the benzodiazepine/GABAA receptor complex activates NO synthase (NOS) to produce NO, which activates soluble guanylyl cyclase (GC-S) to produce cGMP, which, in turn, activates a cyclic GMP-dependent protein kinase, leading to the behavioral effects. This will be accomplished by comparing the behavioral effects of the benzodiazepine chlordiazepoxide, the GABAA agonist 4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol (THIP) and nitrous oxide, another drug of abuse that appears to work at least in part through benzodiazepine/GABAA receptors, in mice following pharmacological manipulation of NOS, NO, guanylyl cyclase, cyclic GMP, and PKG in the CNS. Drug pretreatments will result in reduction in brain NO by inhibition of NOS, restoration of NO in NOS-inhibited brain, inhibition of NO action by an NO scavenger, reduction in brain cGMP by inhibition of GC-S, increase in brain cGMP by inhibition of cGMP degradation, and selective inhibition of protein kinase G (PKG). Other drug challenges will include NO-donors, dibutyryl cGMP and PKG-activators. Methods to be used in this research include behavioral testing in mice (elevated plus-maze and light/dark exploration), central microinjection of pretreatment drugs, and assays to measure cGMP and NOS or PKG enzyme activities. The purpose of the proposed studies is to identify the signaling pathway that mediates benzodiazepine-induced behaviors and provide a progressively more complete understanding, at the molecular level, of the pharmacological and neurochemical mechanisms underlying acute benzodiazepine-induced behaviors.

描述：（申请人摘要） 苯二氮卓类药物是美国最广泛使用的处方药之一， 虽然苯达氮卓类药物在临床上既有效又安全， 尽管如此，人们仍然担心， 这些药物会导致滥用和依赖。 地点和机制 苯二氮卓类药物在中枢神经系统（CNS）中的行为作用 仍然不确定。 拟议的研究旨在测试一种工作 假设药物作用于苯二氮卓类药物引起的行为 氨基丁酸A（GABAA）受体复合物由一氧化氮介导 (NO)/环GMP（cGMP）/蛋白激酶G（PKG）信号通路，即， 刺激苯二氮卓/GABAA受体复合物激活NO 一氧化氮合酶（NOS）产生NO，NO激活可溶性鸟苷酸环化酶 （GC-S）产生cGMP，cGMP反过来激活环GMP依赖性 蛋白激酶，导致行为效应。 这将是 通过比较苯二氮卓类药物 利血平，GABAA激动剂 4，5，6，7-四氢-异恶唑并[5，4-c]吡啶-3-醇（THIP）和一氧化二氮， 另一种滥用药物，似乎至少部分通过 苯二氮卓类/GABAA受体，在小鼠中， CNS中NOS、NO、鸟苷酸环化酶、环GMP和PKG的操纵。 药物预处理可通过抑制脑组织中NO的生成而降低脑组织中NO的含量。 NOS抑制脑中NO的恢复， NO清除剂，通过抑制GC-S减少脑cGMP，增加 通过抑制cGMP降解和选择性抑制 蛋白激酶G（PKG）。 其他药物挑战将包括NO供体， 二丁酰cGMP和PKG激活剂。 本研究中使用的方法 包括小鼠行为测试（高架十字迷宫和光/暗 探索），预处理药物的中央显微注射，以及 测定cGMP和NOS或PKG酶活性。 建议的目的 研究的目的是确定介导 苯二氮卓诱导的行为，并提供一个逐步更完整的 在分子水平上理解药理学和 急性苯二氮卓诱导行为的神经化学机制