ANXIETY--GABA RECEPTOR AND OPIOID GENE TRANSFER

焦虑--GABA受体和阿片类基因转移

• 批准号: 2840565
• 负责人: Marlene A. Wilson
• 金额: $ 7.28万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2840565
• 关键词: GABA receptor; Herpesviridae; amygdala; anxiety disorders; behavior test; benzodiazepines; diazepam; endogenous opioid; enkephalins; gene expression; gene therapy; genetic transduction; laboratory rat; neuropharmacology; opioid receptor; psychopharmacology; tranquilizer; transfection /expression vector

DESCRIPTION: (Adapted From The Applicant's Abstract) The benzodiaepines (BZs) are widely prescribed for the treatment of anxiety-related disorders, although these compounds also have anticonvulsant, hypnotic, and sedative actions. The BZs act at specific receptor sites in the brain to potentiate the actions of the neurotransmitter gamma-aminobutyric acid (GABA). Evidence suggests that the GABA/BZ system in the amygdala may play a critical role in mediating the anxiety-reducing aspects of BZ agonists. Further evidence suggests that the endogenous opioid system also modulates the amygdalar GABAergic system underlying anxiety responses. The proposed studies employ herpes- mediated gene transfer techniques to alter expression of opioid peptides in the rat amygdala. The anxiety levels and the anxiety-reducing effects of BZs will be determined using the elevated plus maze and social interaction tests. Pilot studies using herpes virus vectors encoding either the bacterial protein Beta-galactosidase (virus SHZ.1) or human preproenkephalin (virus SHPE) in the amygdala have demonstrated that 1) we can induce high level expression of the transgenes encoded in these viral vectors in defined brain areas, 2) that viral expression in the amygdala does not have deleterious effects on the animal, 3) that overexpression of enkephalin in the amygdala enhances the anxiolytic effects of the BZs examined using the plus maze, and 4) that we can demonstrate viral expression of the encoded proteins. AIMS 1 and 2 will further characterize the ability of enkephalin overexpression in the amygdala to enhance the anxiety-reducing effects of BZ agonists (diazepam). This includes determining if enkephalin overexpression in amygdala enhances sensitivity to the anxiolytic actions of BZ agonists in another model of anxiety and insuring these effects are mediated through a BZ receptor-dependent mechanism (AIM 1). AIM 2 begins to address the mechanism through which enkephalin overexpression enhances the anxiolytic effects of BZs. Studies examine the opioid receptor subtype involved in this effect of enkephalin, begin to assess which neuronal population is affected in amygdala, and determine if changes in GABA/ BZ receptor sites are observed. Overall, this technique could provide a powerful tool to examine the role of neuropeptides in anxiety- related behaviors, and the anxiolytic action of the BZs. This approach has the marked advantage of altering neurotransmitter or receptor expression in defined brain regions of adult animals. It will thus help to elucidate the role(s) of specific, localized neurotransmitter functions in complex behaviors such as anxiety.

描述：（改编自申请人摘要） 苯二氮卓类药物（BZ）被广泛用于治疗 焦虑相关的疾病，虽然这些化合物也有 抗惊厥、催眠和镇静作用。BZ在特定的 大脑中的受体位点，以增强 神经递质γ-氨基丁酸（GABA）。证据表明 杏仁核中的GABA/BZ系统可能在介导 BZ激动剂减轻焦虑的作用进一步的证据表明 内源性阿片系统也调节杏仁核GABA能神经递质， 系统潜在的焦虑反应。拟议的研究采用疱疹- 改变阿片肽表达的介导基因转移技术 在老鼠的杏仁核里焦虑水平和减轻焦虑的效果 的BZ将使用高架十字迷宫和社交迷宫来确定。 互动测试使用疱疹病毒载体编码 细菌蛋白β-半乳糖苷酶（病毒SHZ.1）或人 杏仁核中的前脑啡肽原（病毒SHPE）已经证明1） 我们可以诱导这些基因编码的转基因的高水平表达， 病毒载体在确定的大脑区域，2）病毒表达在大脑中， 杏仁核对动物没有有害影响，3） 杏仁核中脑啡肽的过度表达增强了抗焦虑作用 使用十字迷宫检查BZ的影响，以及4）我们可以 证明了编码蛋白的病毒表达。目标1和2将 进一步表征脑啡肽过表达的能力， 杏仁核以增强BZ激动剂的减轻焦虑作用 （安定）。这包括确定是否脑啡肽过度表达， 杏仁核增强对BZ激动剂抗焦虑作用的敏感性 在另一个焦虑模型中， 通过BZ受体依赖性机制（AIM 1）。AIM 2开始 探讨脑啡肽过度表达增强 BZ的抗焦虑作用研究检查阿片受体 参与脑啡肽这种作用的亚型，开始评估 杏仁核中的神经元群体受到影响，并确定是否发生变化 在GABA/ BZ受体位点观察到。总的来说，这项技术可以 为研究神经肽在焦虑中的作用提供了有力的工具- 相关行为，以及BZ的抗焦虑作用。这种方法 具有改变神经递质或受体 在成年动物的特定脑区表达。这将有助于 阐明特定、局部神经递质的作用 在复杂行为如焦虑中起作用。