Amygdalar neuropeptides and anxiety

杏仁核神经肽和焦虑

• 批准号: 6660761
• 负责人: Marlene A. Wilson
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6660761
• 关键词: Alphaherpesvirinae; amygdala; anxiety; anxiety disorders; behavior test; benzodiazepines; biological models; biotechnology; buspirone; enkephalins; ethanol; fear; gene expression; genetically modified animals; immunocytochemistry; laboratory rat; neuropeptides; neuropharmacology; opioid receptor; psychopharmacology; radioimmunoassay; tranquilizer; transfection; transfection /expression vector

DESCRIPTION (provided by applicant): The amygdala is a brain structure that plays a crucial role in fear and anxiety, and the actions of anxiety-reducing compounds. The opioid peptide has also been shown to modulate anxiety-related responses within the amygdala. Using herpes virus-mediated gene transfer, we have demonstrated that overexpression of enkephalin in the amygdala enhances the anxiety-reducing influences of the benzodiazepine diazepam (Valium) in rats. These initial results demonstrate that herpes virus-mediated gene transfer can transiently alter expression of neuropeptides in confined brain sites of adult rats, and that these changes can modify behavioral responses. The present studies continue to utilize this powerful technique to examine the role of amygdalar enkephalin in regulating anxiety-related behaviors and the actions of anxiolytic drugs. Both decreases and cell-targeted increases in peptide expression will be examined in several animal models of anxiety. Aim 1 will verify the ability of virus-mediated gene transfer to decrease and cell-specifically increase expression of enkephalin in select areas of amygdala. Anatomical and quantitative methods will assess changes in mRNA expression, while peptide changes will be assessed with immunohistochemistry and radioimmunoassay. AIM 2 examines if altered enkephalin expression in central amygdala modifies anxiety-related behaviors in additional animal tests of anxiety behaviors and/or the effectiveness of other anxiolytics in these tests. These studies 1) compare decreases with cell-specific increases in enkephalin expression, 2) test the activity of other anxiolytics (alcohol, the serotonergic compound buspirone), and 3) tests effects in several models of anxiety. AIM 3 assesses the effects of pharmacological modulation of enkephalin activity in amygdala. Using more traditional techniques selective opioid receptor (mu, delta) agonists and antagonists will be locally applied in amygdala, and the effect of these compounds on responses to anxiolytic drugs will be tested. These studies will lead to a better understanding of the role of amygdala and enkephalin in anxiety and anxiolytic responses, as well as elucidate the differences between animal models of anxiety. This understanding may also suggest novel, avenues for development of treatments for anxiety or affective disorders.

描述（由申请人提供）：杏仁核是一种大脑结构，在恐惧和焦虑以及减轻焦虑的化合物的作用中发挥着至关重要的作用。阿片肽也被证明可以调节杏仁核内与焦虑相关的反应。利用疱疹病毒介导的基因转移，我们证明杏仁核中脑啡肽的过度表达增强了苯二氮卓类地西泮（安定）对大鼠的减轻焦虑的作用。这些初步结果表明，疱疹病毒介导的基因转移可以暂时改变成年大鼠受限大脑部位神经肽的表达，并且这些变化可以改变行为反应。目前的研究继续利用这种强大的技术来检查杏仁核脑啡肽在调节焦虑相关行为和抗焦虑药物的作用中的作用。将在几种焦虑动物模型中检查肽表达的减少和细胞靶向的增加。目标 1 将验证病毒介导的基因转移在杏仁核选定区域中减少和细胞特异性增加脑啡肽表达的能力。解剖学和定量方法将评估 mRNA 表达的变化，而肽的变化将通过免疫组织化学和放射免疫测定进行评估。 AIM 2 检查杏仁核中央脑啡肽表达的改变是否会改变额外的焦虑行为动物测试中的焦虑相关行为和/或这些测试中其他抗焦虑药的有效性。这些研究 1) 比较脑啡肽表达的减少与细胞特异性的增加，2) 测试其他抗焦虑药（酒精、血清素化合物丁螺环酮）的活性，3) 测试几种焦虑模型的效果。 AIM 3 评估杏仁核中脑啡肽活性的药理调节作用。使用更传统的技术，选择性阿片受体（μ、δ）激动剂和拮抗剂将局部应用于杏仁核，并测试这些化合物对抗焦虑药物反应的影响。这些研究将有助于更好地了解杏仁核和脑啡肽在焦虑和抗焦虑反应中的作用，并阐明焦虑动物模型之间的差异。这种理解还可能为开发焦虑或情感障碍的治疗方法提供新的途径。