Amygdalar Neuropeptides and Anxiety

杏仁核神经肽和焦虑

基本信息

批准号：
7686186
负责人：
JIM R FADEL
金额：
$ 31.66万
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：
2002
资助国家：
美国
起止时间：
2002-09-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7686186
关键词：
Abbreviations Adult Affect Affective Agonist Alcohols Amygdaloid structure Animal Model Anti-Anxiety Agents Anxiety Anxiety Disorders Behavior Behavioral Benzodiazepines Brain imaging Brain region CRH gene Calcium Calcium/calmodulin-dependent protein kinase Calmodulin Cell Nucleus Cells Chemicals Cholecystokinin Clinical Corticotropin-Releasing Hormone Cues Data Disease Drug usage Dynorphins Emotional Endocrine Enkephalins Freezing Fright Gene Transfer Glutamate Decarboxylase Glutamates Gray unit of radiation dose Green Fluorescent Proteins Immunohistochemistry In Situ Hybridization Infusion procedures Intercalated Cell Interneurons Label Lead Learning Location Medial Mediating Mental disorders Methodology Microdialysis Modeling Mood Disorders Morphine Neurons Neuropeptides Odors Opiates Opioid Opioid Peptide Opioid Receptor Output Parvalbumins Patients Pattern Pharmaceutical Preparations Phenotype Population Process Radioimmunoassay Receptor Activation Regulation Role Simplexvirus Somatostatin Stimulus Structure of terminal stria nuclei of preoptic region Subfamily lentivirinae System Testing Vasoactive Intestinal Peptide Virus Withdrawal base calretinin chronic pain conditioned fear delta opioid receptor drug of abuse gamma-Aminobutyric Acid hippocampal pyramidal neuron immunoreactivity in vivo interdisciplinary approach kappa opioid receptors mu opioid receptors neural circuit neuropeptide Y novel therapeutics opioid abuse postsynaptic preproenkephalin presynaptic receptor receptor expression relating to nervous system response restraint stress treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Anxiety and affective disorders represent an important clinical problem, yet our understanding of the disorders and the drugs used to treat them remains limited. Brain imaging studies show amygdala changes in patients with these disorders. The present studies use a multifaceted approach to elucidate how amygdalar opioid systems regulate anxiety and fear-related processes. These studies will enhance our understanding of amygdala circuits that control distinct aspects of anxiety and fear by comparing several anxiety-evoking stimuli, and elucidate the specific role of mu opioid receptors (MOR) in these different responses. Since our previous studies suggested that mu opioid receptors (MOR) and enkephalin in the amygdala can modulate basal anxiety responses and the actions of benzodiazepine anxiolytic drugs, the proposed studies will examine how MOR receptors modulate amygdalar circuitry to alter these anxiety-related responses. We hypothesize that distinct neuronal circuits are activated by different conditioned and unconditioned anxiety-evoking situations, and that presynaptic MOR receptors localized in specific amygdalar neurocircuits regulate changes in amygdala glutamate and GABA release to shift anxiety-related responses in a context-dependent manner. Four anxiety-evoking tests, including the elevated plus maze (unpredictable threat), predator odor-induced defensive burying (specific threat), restraint stress (psychogenic stimulus) and cue- conditioned freezing (learned fear), will be compared in these studies. Aim 1 uses virus-mediated gene transfer to examine if decreasing the expression of MOR in the amygdala alters anxiety-related behaviors and/or endocrine responses to restraint stress, and if selectively targeting these decreases to pyramidal neurons of the basolateral amygdala produces the same effects. Aim 2 uses cFos immunoreactivity to compare the cellular phenotype(s) activated by distinct anxiety-evoking situations, the localization of MOR in these activated neuron populations, and if activation patterns are altered by decreasing amygdala MOR expression. Aim 3 uses in vivo microdialysis in the amygdala to assess 1) if MOR activation alters GABA or glutamate efflux, 2) if anxiety-evoking situations induce release of enkephalin, GABA, or glutamate, and 3) if decreasing MOR expression modifies MOR-induced or anxiety-induced release of GABA or glutamate. The studies will enhance our understanding of how the amygdala and the opioid system regulate anxiety responses, and could provide novel therapeutic strategies for treating affective and anxiety-related disorders. Since opioid systems in the amygdala are modified during chronic pain states and altered by drugs of abuse, the results of these studies will also enhance our understanding of the neural basis of heightened anxiety states seen in chronic pain patients or during withdrawal from opiates, benzodiazepines, and alcohol. Anxiety disorders are the most common mental illness and affect more than19 million US adults, yet our understanding of these disorders and the drugs used to treat them remains limited. The present studies use animal models to elucidate how the circuitry in the brain region underlying emotional behaviors, namely the amygdala, controls responses in three different anxiety-evoking situations. The focus on endogenous morphine-like chemicals (opioids) could lead to new treatment strategies for anxiety disorders, and increase our understanding of why chronic pain states or withdrawal from prescribed or abused opioid drugs lead to increased anxiety.

描述（由申请人提供）：焦虑和情感障碍是一个重要的临床问题，但是我们对治疗它们的疾病和药物的理解仍然有限。脑成像研究表明，这些疾病患者的杏仁核变化。本研究采用多方面的方法来阐明杏仁核阿片类系统如何调节焦虑和与恐惧相关的过程。这些研究将增强我们对杏仁核电路的理解，通过比较几种焦虑诱发的刺激，并阐明MU阿片受体（MOR）在这些不同的反应中的特定作用，从而控制焦虑和恐惧的不同方面。由于我们先前的研究表明，杏仁核中的MU阿片受体（MOR）和Enkephalin可以调节基础焦虑反应以及苯二氮卓类抗焦虑药的作用，因此拟议的研究将检查MOR受体如何调查杏仁核电路如何改变这些与焦虑相关的反应。我们假设不同的神经元回路被不同的条件和无条件的焦虑诱发情况激活，并且在特定杏仁核神经电路中定位的突触前MOR受体调节杏仁核和GABA释放杏仁核的变化，以在上下文依赖的方式中释放焦虑相关的反应。在这些研究中，将进行四项焦虑诱发的测试，包括升高的迷宫（不可预测的威胁），捕食者气味引起的防御性埋葬（特定的威胁），克制压力（精神刺激）和有条件的冻结（学习的恐惧）。 AIM 1使用病毒介导的基因转移来检查杏仁核中MOR的表达是否会改变与焦虑相关的行为和/或对约束压力的内分泌反应，并且是否选择性地靶向这些降低对基底外侧Amygdala的锥体神经元会产生相同的效应。 AIM 2使用CFOS免疫反应性来比较通过明显的焦虑诱发情况激活的细胞表型，在这些激活的神经元种群中MOR的定位，以及是否通过降低杏仁核MOR表达来改变激活模式。 AIM 3在杏仁核中使用体内微透析来评估1）1）如果MOR激活改变了GABA或谷氨酸外排，2）如果焦虑诱发的情况会诱发Enkephalin，Gaba或Grutamamate的释放，以及3）如果减少Mor表达会改变Mor的表达，则或焦虑引起的GABA或谷氨酸释放。这些研究将增强我们对杏仁核和阿片类药物系统如何调节焦虑反应的理解，并可以为治疗情感和焦虑相关疾病提供新颖的治疗策略。由于杏仁核中的阿片类药物系统在慢性疼痛状态下经过修饰，并因滥用药物而改变，因此这些研究的结果还将增强我们对慢性疼痛患者中焦虑状态增强的神经基础的理解，或者在退出阿片类药物，苯二氮卓，苯二氮卓，，苯二氮卓，和酒精。焦虑症是最常见的精神疾病，影响了超过1,900万美国成年人，但是我们对这些疾病和用于治疗它们的药物的理解仍然有限。本研究使用动物模型来阐明情绪行为的基本电路（即杏仁核）如何控制三种不同焦虑的情况下的反应。对内源性吗啡样化学物质（阿片类药物）的关注可能会导致焦虑症的新治疗策略，并增加我们对为什么慢性疼痛状态或从处方或滥用阿片类药物中戒断的原因导致焦虑增加的理解。