Stress-induced locus coeruleus dysfunction as a mediator of opioid abuse

项目摘要 阿片类药物滥用和焦虑症是美国最普遍的精神疾病之一， 诊断出一种会增加另一种的风险。鉴于它们的重叠和目前的状态， 由于阿片类药物流行病困扰着该国，因此澄清将这两者联系起来的机制至关重要 条件蓝斑核（locus coeruleus，LC）是脑干的一个核团，广泛参与中枢神经系统的活动 功能协调发展的压力激活LC并促进高度警惕的焦虑样行为。虽然许多研究在 过去已经研究了应力如何在短时间间隔内影响LC的功能，但对应力如何影响LC的功能知之甚少。 应激源暴露会导致细胞核的长期变化， 行为状态我们实验室最近的观察表明，急性创伤性应激源可以产生 焦虑样行为和LC活性的长期升高，此外，这些影响可能与 LC阿片受体的功能改变。这是非常重要的，因为内源性阿片样物质 LC中的信号传导有助于终止应激反应，减少LC活动，并促进恢复到非焦虑状态。 行为状态因此，如果应激减弱了LC中阿片受体的功能，内源性阿片可能不会被抑制。 足以将LC放电限制在不促进焦虑的水平。在这种情况下，有前科的人 慢性或创伤性应激障碍的患者可能倾向于使用滥用的阿片类药物，因为它们能够有效地 抑制LC。此外，从阿片类药物依赖中恢复过来的人可能会在以下情况下复发： 面对新的压力源因此，了解应激暴露对LC功能和阿片类药物的影响， 信号，以及内源性阿片信号在动机行为中的作用，可能会提供关于 治疗方法，以抵消一些异常行为中看到的共病焦虑和阿片类药物的使用 紊乱该项目的目标是首先表明，在LC中增强阿片样物质信号传导是抗焦虑的， 在经历过压力的动物中加强，因为它如何减少LC多动，因此 负面情绪其次，我们的目标是表明，创伤性压力也使动物更容易自我， 因为压力引起的LC变化而滥用阿片类药物。假设压力增加 与焦虑相关的LC活性，并降低LC被内源性阿片类药物抑制的能力。 因此，动物将参与导致人为增强的内源性阿片样物质信号传导的行为， 递送静脉内滥用的阿片类药物，因为它们能够减少LC活动过度。的结果予以 实验将证明，在经典成瘾回路之外， 有能力使动物更有可能自我管理滥用阿片类药物。这些发现将具有重要意义 对焦虑和阿片类药物使用障碍的机制和治疗的影响。

Project Summary Opioid abuse and anxiety disorders are amongst the most prevalent psychiatric conditions in the United States, and diagnosis of one increases the risk of developing the other. Given their overlap and the current state of the opioid epidemic gripping the country, it is of critical importance to clarify the mechanisms that link these two conditions. The locus coeruleus (LC) is a brainstem nucleus involved in a wide array of central nervous system functions. Stress activates LC and promotes hypervigilant anxiety-like behavior. Although many studies in the past have investigated how stress affects the function of the LC at short intervals, less is known about how stressor exposure causes long term changes in the nucleus that are associated with a chronically altered behavioral state. Recent observations from our laboratory show that an acute traumatic stressor can produce long-lasting elevations in anxiety-like behavior and LC activity, and furthermore, these effects may be related to altered function of LC opioid receptors. This is of great importance due to the fact that endogenous opioid signaling in LC helps terminate the stress response, reduce LC activity, and promote a return to a non-anxious behavioral state. Thus, if stress blunts the function of opioid receptors in LC, endogenous opioids may not be sufficient to limit LC discharge to levels that do not promote anxiety. In this scenario, individuals with a history of chronic or traumatic stress might be predisposed to use abused opioids, because of their ability to potently inhibit LC. Furthermore, individuals who have recovered from opioid dependence might be likely to relapse when faced with a new stressor. Therefore, understanding the impact of stressor exposure on LC function and opioid signaling, and the role of endogenous opioid signaling in motivated behavior, may provide insights towards therapeutic approaches to counteract some of the abnormal behaviors seen in comorbid anxiety and opioid use disorders. The goals of this project are first to show that enhancing opioid signaling in LC is anxiolytic and reinforcing in animals that have experienced stress because of how it reduces LC hyperactivity, and therefore negative emotion. Second, we aim to show that traumatic stress also makes animals more likely to self- administer abused opioids because of stress-induced changes in LC. The hypothesis is that stress increases LC activity, which correlates with anxiety, and reduces the ability of LC to be inhibited by endogenous opioids. Therefore, animals will engage in behaviors that lead to artificially enhanced endogenous opioid signaling or delivery of intravenously abused opioids, because of their ability to reduce LC hyperactivity. The results of these experiments will demonstrate that a stress-induced neuroadaptation outside of the classical addiction circuitry has the ability make animals more likely to self-administer abused opioids. Such findings would have important implications for mechanisms of and treatments for both anxiety and opioid use disorders.