Amygdalar neuropeptides and anxiety

描述(申请人提供)：杏仁核是一种大脑结构，在恐惧和焦虑以及降低焦虑的化合物的活动中发挥关键作用。阿片肽还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，我们已经证明脑啡肽在杏仁核的过度表达增强了苯二氮卓类安定(安定)对大鼠的焦虑缓解作用。这些初步结果表明，疱疹病毒介导的基因转移可以瞬时改变成年大鼠受限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一强大的技术来研究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。在几种焦虑的动物模型中，将检测多肽表达的减少和细胞靶标的增加。目的1将验证病毒介导的基因转移在杏仁核特定区域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，而多肽的变化将通过免疫组织化学和放射免疫分析来评估。目的2检验杏仁中央核脑啡肽表达的改变是否改变了焦虑行为的动物实验中的焦虑相关行为和/或其他抗焦虑药物在这些实验中的有效性。这些研究1)比较脑啡肽表达的减少和细胞特异性的增加，2)测试其他抗焦虑药物(酒精，5-羟色胺能化合物丁螺环酮)的活性，3)测试几种焦虑模型的效果。目的3评价药物对杏仁核脑啡肽活性的调节作用。使用更传统的技术，选择性阿片受体(u，Delta)激动剂和拮抗剂将局部应用于杏仁核，这些化合物对抗焦虑药物的反应的影响将被测试。这些研究将有助于更好地理解杏仁核和脑啡肽在焦虑和焦虑反应中的作用，并阐明焦虑动物模型之间的差异。这一理解也可能为开发治疗焦虑症或情感性障碍的新途径提供建议。

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.