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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要阿片类药物滥用和焦虑症是美国最普遍的精神病患者之一一个人的诊断增加了发展对方的风险。考虑到它们的重叠和当前状态阿片类药物流行诱使该国，澄清将这两者联系起来的机制至关重要状况。基因座（LC）是与广泛的中枢神经系统有关的脑干核功能。应力激活LC并促进过度焦虑样行为。尽管许多研究过去已经调查了压力如何在短时间间隔影响LC的功能，对如何如何了解压力源暴露会导致核的长期变化，这与慢性变化有关行为状态。我们实验室的最新观察结果表明，急性创伤应力可以产生焦虑行为和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。由于内源性阿片类药物，这非常重要 LC中的信号传导有助于终止压力反应，减少LC活性并促进返回到非焦虑的行为状态。因此，如果压力钝化LC中阿片受体的功能，则内源性阿片类药物可能不是足以将LC排放限制为不会促进焦虑的水平。在这种情况下，有历史的人慢性或创伤性压力可能会倾向于使用滥用的阿片类药物，因为它们有能力抑制LC。此外，从阿片类药物依赖中恢复过的人可能会复发面对新的压力源。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药物信号在动机行为中的作用，可能会提供见解治疗方法来抵消合并症和阿片类药物使用中的某些异常行为疾病。该项目的目标首先表明LC中增强阿片类药物的信号传导是抗焦虑性和加强由于它如何减少LC的多动症而造成压力的动物，因此负面情绪。其次，我们的目的是表明创伤压力也使动物更有可能自我自我由于压力引起的LC变化，因此滥用阿片类药物。假设是压力增加 LC活性与焦虑相关，并降低了内源性阿片类药物抑制LC的能力。因此，动物将从事人为增强的内源性阿片类药物信号传导或静脉滥用阿片类药物的递送，因为它们能够减少LC多动症。这些结果实验将表明，在经典成瘾电路之外，应力引起的神经适应具有使动物更有可能自我滥用阿片类药物的能力。这样的发现很重要对焦虑和阿片类药物使用障碍的机制和治疗的影响。