ANXIETY--GABA RECEPTOR AND OPIOID GENE TRANSFER

焦虑--GABA受体和阿片类基因转移

基本信息

批准号：
6151502
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
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-01 至 2002-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6151502
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

项目摘要

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：（改编自申请人的摘要）苯二氮卓类药物 (BZ) 广泛用于治疗焦虑相关的疾病，尽管这些化合物也有抗惊厥、催眠和镇静作用。 BZ 的作用具体为大脑中的受体位点，以增强神经递质γ-氨基丁酸（GABA）。有证据表明杏仁核中的 GABA/BZ 系统可能在调节中发挥关键作用 BZ 激动剂的减轻焦虑作用。进一步的证据表明内源性阿片系统也调节杏仁核 GABA 能系统潜在的焦虑反应。拟议的研究采用疱疹- 介导的基因转移技术改变阿片肽的表达在大鼠杏仁核中。焦虑水平和减轻焦虑的效果 BZ 的数量将使用高架十字迷宫和社交来确定交互测试。使用疱疹病毒载体编码的试点研究细菌蛋白β-半乳糖苷酶（病毒SHZ.1）或人类杏仁核中的前脑啡肽原（病毒 SHPE）已证明 1) 我们可以诱导这些编码的转基因的高水平表达病毒载体在特定的大脑区域，2）病毒表达在杏仁核不会对动物产生有害影响，3）杏仁核中脑啡肽的过度表达可增强抗焦虑作用使用十字迷宫检查 BZ 的效果，以及 4) 我们可以证明编码蛋白的病毒表达。目标 1 和 2 将进一步表征脑啡肽过度表达的能力杏仁核增强 BZ 激动剂的减轻焦虑作用（地西泮）。这包括确定脑啡肽是否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种焦虑模型中并确保这些影响得到调节通过 BZ 受体依赖性机制 (AIM 1)。 AIM 2 开始解决脑啡肽过度表达增强的机制 BZ 的抗焦虑作用。研究检查阿片受体参与脑啡肽作用的亚型，开始评估哪种亚型杏仁核中的神经元群体受到影响，并确定是否发生变化观察到 GABA/BZ 受体位点。总体而言，该技术可以提供了一个强大的工具来检查神经肽在焦虑中的作用相关行为以及 BZ 的抗焦虑作用。这种做法具有改变神经递质或受体的显着优势在成年动物的特定大脑区域中表达。这将有助于阐明特定的局部神经递质的作用在焦虑等复杂行为中发挥作用。