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：（根据申请人的摘要改编）苯二二炎（BZ）被广泛规定用于治疗尽管这些化合物也具有与焦虑有关的疾病抗惊厥药，催眠和镇静作用。 BZS法案大脑中的受体位点增强了神经递质γ-氨基丁酸（GABA）。有证据表明这一点杏仁核中的GABA/BZ系统可能在调解中起关键作用 BZ激动剂的减轻焦虑方面。进一步的证据表明内源性阿片类药物系统还调节杏仁核GABA能焦虑反应的基础系统。拟议的研究采用疱疹 - 介导的基因转移技术改变阿片类肽的表达在大鼠杏仁核中。焦虑水平和减轻焦虑的影响 BZ将使用高架的迷宫和社会来确定交互测试。使用疱疹病毒载体编码的试验研究细菌蛋白β-半乳糖苷酶（病毒SHZ.1）或人杏仁核中的前脑瘤（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定义的大脑区域中的病毒向量，2）杏仁核对动物没有有害影响，3）杏仁核中ankephalin的过表达增强了抗焦虑使用Plus迷宫检查的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将进一步表征了ankephalin过表达的能力杏仁核增强BZ激动剂的减轻焦虑症（地西epa）。这包括确定ankephalin是否过表达杏仁核增强了对BZ激动剂抗焦虑作用的敏感性在另一种焦虑和确保这些效果的模型中是介导的通过BZ受体依赖性机制（AIM 1）。目标2开始解决ankephalin过表达增强的机制 BZ的抗焦虑作用。研究检查阿片类药物受体参与Enkephalin的这种影响的亚型，开始评估哪个神经元种群在杏仁核中受到影响，并确定是否发生了变化在GABA/ Bz受体位点中。总的来说，这项技术可以提供了一种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。这种方法具有改变神经递质或受体的明显优势在成年动物的明确大脑区域中的表达。因此会有所帮助阐明特定的局部神经递质的作用在诸如焦虑之类的复杂行为中发挥作用。