Amygdalar Neuropeptides and Anxiety

杏仁核神经肽和焦虑

• 批准号: 7523990
• 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
• 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/7523990
• 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; Condition; Corticotropin-Releasing Hormone; Cues; Data; Disease; Drug Use Disorder; Dynorphins; Emotional; Endocrine; Enkephalin Receptors; 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; Localized; Location; Medial; Mediating; Mental disorders; Methodology; Microdialysis; Modeling; Mood Disorders; Morphine; Neurons; Neuropeptides; Odors; Opiates; Opioid; Opioid Peptide; Opioid Receptor; Output; PAG gene; 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; human PAG protein; 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

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，但我们对这些疾病和用于治疗它们的药物的了解仍然有限。脑成像研究显示患有这些疾病的患者杏仁核发生变化。目前的研究采用多方面的方法来阐明杏仁核阿片类药物系统如何调节焦虑和恐惧相关的过程。这些研究将通过比较几种引起焦虑的刺激，增强我们对控制焦虑和恐惧不同方面的杏仁核回路的理解，并阐明 mu 阿片受体 (MOR) 在这些不同反应中的具体作用。由于我们之前的研究表明杏仁核中的μ阿片受体（MOR）和脑啡肽可以调节基础焦虑反应和苯二氮卓类抗焦虑药物的作用，因此拟议的研究将探讨MOR受体如何调节杏仁核回路以改变这些与焦虑相关的反应。我们假设不同的条件性和非条件性焦虑诱发情况会激活不同的神经元回路，并且位于特定杏仁核神经回路中的突触前 MOR 受体调节杏仁核谷氨酸和 GABA 释放的变化，从而以上下文依赖性方式改变焦虑相关反应。这些研究将比较四项引发焦虑的测试，包括高架十字迷宫（不可预测的威胁）、捕食者气味引起的防御掩埋（特定威胁）、约束压力（心源性刺激）和线索条件冻结（习得性恐惧）。目标 1 使用病毒介导的基因转移来检查减少杏仁核中 MOR 的表达是否会改变焦虑相关行为和/或对束缚压力的内分泌反应，以及选择性地将这些减少针对基底外侧杏仁核的锥体神经元是否会产生相同的效果。目标 2 使用 cFos 免疫反应性来比较由不同的焦虑诱发情况激活的细胞表型、MOR 在这些激活的神经元群体中的定位，以及激活模式是否因杏仁核 MOR 表达的减少而改变。目标 3 使用杏仁核体内微透析来评估 1) MOR 激活是否会改变 GABA 或谷氨酸流出，2) 焦虑诱发情况是否会诱导脑啡肽、GABA 或谷氨酸释放，3) 减少 MOR 表达是否会改变 MOR 诱导或焦虑诱导的 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会发生改变，并且会因滥用药物而改变，因此这些研究的结果也将增强我们对慢性疼痛患者或戒断阿片类药物、苯二氮卓类药物和酒精期间出现的高度焦虑状态的神经基础的理解。焦虑症是最常见的精神疾病，影响着超过 1900 万美国成年人，但我们对这些疾病以及用于治疗这些疾病的药物的了解仍然有限。目前的研究使用动物模型来阐明情绪行为背后的大脑区域（即杏仁核）如何控制三种不同的焦虑诱发情况下的反应。对内源性吗啡类化学物质（阿片类药物）的关注可能会带来治疗焦虑症的新策略，并增加我们对为什么慢性疼痛状态或戒断处方或滥用阿片类药物会导致焦虑加剧的理解。