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，然而我们对这些疾病和用于治疗它们的药物的理解仍然有限。脑成像研究显示，这些疾病患者的杏仁核发生了变化。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，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mu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，因此我们提出的研究将研究MOR受体如何调节杏仁核回路以改变这些焦虑相关反应。我们假设不同的神经回路被不同的条件和非条件的焦虑诱发情况激活，并且定位于特定杏仁核神经回路的突触前MOR受体调节杏仁核谷氨酸和GABA释放的变化，以情境依赖的方式改变焦虑相关反应。四种引起焦虑的测试，包括升高+迷宫（不可预测的威胁）、捕食者气味诱导的防御掩埋（特定威胁）、约束压力（心理刺激）和线索条件冻结（习得性恐惧），在这些研究中进行了比较。目的1使用病毒介导的基因转移来检测降低杏仁核中MOR的表达是否会改变焦虑相关行为和/或对约束应激的内分泌反应，以及是否选择性地将这些减少靶向于杏仁核基底外侧锥体神经元产生相同的效果。目的2使用cFos的免疫反应性来比较不同焦虑诱发情况下激活的细胞表型，MOR在这些激活的神经元群体中的定位，以及激活模式是否通过减少杏仁核MOR表达而改变。目的3在杏仁核中使用体内微透析来评估1)MOR激活是否改变GABA或谷氨酸外排，2)引起焦虑的情况是否诱导脑啡肽、GABA或谷氨酸的释放，以及3)MOR表达减少是否改变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障碍提供新的治疗策略。由于杏仁核中的阿片系统在慢性疼痛状态下被改变，并因药物滥用而改变，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时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1900多万美国成年人，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中隐藏情绪行为的区域，即杏仁核，如何控制三种不同的焦虑唤起情况下的反应。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戒断处方或滥用阿片类药物会导致焦虑增加的理解。

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.