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常见的精神疾病之一， 其中一种疾病的诊断会增加患另一种疾病的风险。考虑到它们的重叠以及 在阿片类药物流行席卷全国之际，至关重要的是澄清这两者之间的联系机制 条件。蓝斑(LC)是一种脑干核团，参与多种中枢神经系统 功能。压力会激活LC，并促进高度警惕的焦虑样行为。虽然许多研究都是在 过去已经研究了压力如何以短时间间隔影响LC的功能，但关于压力如何影响LC的功能知之甚少 应激源暴露导致核团的长期变化，这与慢性改变有关 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活动的长期升高，而且这些影响可能与 LC阿片受体功能改变。这一点非常重要，因为内源性阿片类药物 LC中的信号有助于终止应激反应，减少LC活动，并促进向非焦虑状态的回归 行为状态。因此，如果压力削弱了LC中阿片受体的功能，内源性阿片类药物可能不会 足以将LC放电限制在不会引发焦虑的水平。在这种情况下，有历史的个人 慢性或创伤性应激的患者可能倾向于使用滥用的阿片类药物，因为他们有能力 抑制LC。此外，在以下情况下，已经从阿片依赖中恢复过来的人可能会复发 面对新的压力源。因此，了解应激源暴露对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，可能为 消除焦虑和阿片类药物共用中的一些异常行为的治疗方法 精神错乱。这个项目的目标是首先证明增强LC中的阿片信号是抗焦虑和 在经历过压力的动物中强化，因为它可以减少LC多动，因此 负面情绪。第二，我们的目标是证明创伤应激也使动物更有可能自我 使用滥用阿片类药物是因为压力引起LC的改变。假设是压力会增加 LC活性与焦虑相关，并降低LC被内源性阿片类药物抑制的能力。 因此，动物将从事导致人为增强内源性阿片信号或 静脉注射滥用阿片类药物，因为它们有能力减少LC过度活动。这些研究的结果 实验将证明，在经典的成瘾回路之外，压力诱导的神经适应 有能力使动物更有可能自我给药滥用阿片类药物。这样的发现将具有重要的 焦虑症和阿片类药物使用障碍的机制和治疗的意义。

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.