Amygdalar Neuropeptides and 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会发生变化。目前的研究使用多方面的方法来阐明杏仁核阿片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来增强我们对控制焦虑和恐惧的不同方面的杏仁核回路的理解，并阐明μ阿片受体（莫尔）在这些不同反应中的特定作用。由于我们以前的研究表明，μ阿片受体（莫尔）和脑啡肽在杏仁核可以调节基础焦虑反应和苯二氮卓类抗焦虑药物的作用，拟议的研究将检查莫尔受体如何调节杏仁核电路，以改变这些焦虑相关的反应。我们假设，不同的神经元回路激活不同的条件和非条件焦虑诱发的情况下，和突触前莫尔受体定位在特定的杏仁核神经回路调节杏仁核谷氨酸和GABA释放的变化，以改变焦虑相关的反应，在一个上下文依赖的方式。四个焦虑诱发测试，包括高架十字迷宫（不可预测的威胁），捕食者气味诱导的防御性埋葬（特定威胁），约束压力（心因性刺激）和线索条件冻结（学习恐惧），将在这些研究中进行比较。目的1使用病毒介导的基因转移，以检查是否减少莫尔在杏仁核的表达改变焦虑相关的行为和/或内分泌反应的约束压力，如果选择性地针对这些减少基底外侧杏仁核的锥体神经元产生相同的效果。目的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、莫尔在这些激活的神经元群体中的定位以及激活模式是否通过减少杏仁核莫尔表达而改变。目的3在杏仁核中使用体内微透析来评估1）莫尔激活是否改变GABA或谷氨酸的流出，2）焦虑诱发情况是否诱导脑啡肽、GABA或谷氨酸的释放，以及3）降低莫尔表达是否改变MOR诱导或焦虑诱导的GABA或谷氨酸的释放。这些研究将加深我们对杏仁核和阿片系统如何调节焦虑反应的理解，并可能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系统在慢性疼痛状态下被修改，并被滥用药物改变，这些研究的结果也将增强我们对慢性疼痛患者或阿片类药物、苯二氮卓类药物和酒精戒断期间焦虑状态加剧的神经基础的理解。焦虑症是最常见的精神疾病，影响超过1900万美国成年人，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。目前的研究使用动物模型来阐明大脑区域中的回路，即杏仁核，在三种不同的焦虑诱发情况下控制情绪行为的反应。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，并增加我们对慢性疼痛状态或从处方或滥用阿片类药物中戒断导致焦虑增加的原因的理解。

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.