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

应激引起的蓝斑功能障碍是阿片类药物滥用的中介因素

• 批准号: 10303890
• 负责人: Daniel Chandler
• 金额: $ 25.37万
• 依托单位: ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303890
• 关键词: Acute; Advanced Development; Affect; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological Assay; Brain; Brain Stem; Burial; Cell Nucleus; Chronic; Chronic stress; Control Animal; Country; Data; Diagnosis; Disease; Dopamine; Dose; Down-Regulation; Emotions; Enkephalin Receptors; Enkephalins; Female; Fiber; Functional disorder; Future; Generations; Goals; Human; Hyperactivity; Individual; Infusion procedures; Intravenous; Investigation; Laboratories; Lead; Learning; Link; Measures; Mediating; Mediator of activation protein; Naloxone; Nervous System Physiology; Neuraxis; Norepinephrine; Opiate Addiction; Opioid; Opioid Antagonist; Opioid Receptor; Oxycodone; Pathway interactions; Pharmaceutical Preparations; Physiology; Play; Prosencephalon; Public Health; Rattus; Recording of previous events; Relapse; Research; Rewards; Risk; Rodent; Role; Self Administration; Shock; Signal Transduction; Site; Speed; Stress; Structure; Testing; Therapeutic; Time; United States; Viral; Withdrawal; addiction; anxiety-like behavior; base; biological adaptation to stress; comorbidity; drug seeking behavior; dysphoria; endogenous opioids; experience; experimental study; insight; locus ceruleus structure; male; mesolimbic system; motivated behavior; neuroadaptation; neurobiological mechanism; novel; opioid abuse; opioid epidemic; opioid use; opioid use disorder; overexpression; preference; preproenkephalin; promoter; receptor; resilience; response; reward circuitry; sex; stressor; traumatic stress

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.

项目概要 阿片类药物滥用和焦虑症是美国最普遍的精神疾病之一， 一种疾病的诊断会增加患另一种疾病的风险。鉴于它们的重叠和当前状态 阿片类药物流行病困扰该国，阐明将这两者联系起来的机制至关重要 状况。蓝斑 (LC) 是脑干核，参与广泛的中枢神经系统 功能。压力会激活 LC 并促进过度警惕的焦虑样行为。尽管许多研究在 过去已经研究了压力如何在短时间内影响 LC 的功能，但对于如何影响 LC 的功能知之甚少。 应激源暴露会导致细胞核发生长期变化，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 活动的长期持续升高，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，因为内源性阿片类药物 LC 中的信号传导有助于终止应激反应、减少 LC 活性并促进恢复到非焦虑状态。 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发挥作用。 足以将 LC 放电限制在不会加剧焦虑的水平。在这种情况下，有历史的个人 慢性或创伤性压力的人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的个体可能会在以下情况下复发： 面临新的压力源。因此，了解压力源暴露对 LC 功能和阿片类药物的影响 信号传导以及内源性阿片类信号传导在动机行为中的作用，可能会为以下方面提供见解： 治疗方法来抵消共病焦虑和阿片类药物使用中出现的一些异常行为 失调。该项目的目标首先是证明增强 LC 中的阿片类药物信号传导具有抗焦虑作用，并且 由于它可以减少 LC 过度活跃，因此可以对经历过压力的动物进行强化，因此 负面情绪。其次，我们的目标是证明创伤性压力也会使动物更有可能自我攻击 由于压力引起的 LC 变化而施用滥用的阿片类药物。假设压力会增加 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，动物会采取导致人为增强内源性阿片类信号传导或 静脉注射滥用的阿片类药物，因为它们能够减少 LC 过度活跃。这些结果 实验将证明经典成瘾回路之外的压力诱导的神经适应 具有使动物更有可能自行施用滥用阿片类药物的能力。这些发现将具有重要意义 对焦虑症和阿片类药物使用障碍的机制和治疗的影响。