Noradrenergic Plasticity in Opioid Withdrawal

阿片类药物戒断中的去甲肾上腺素能可塑性

基本信息

批准号：
9973280
负责人：
Zoe Anastasia McElligott
金额：
$ 42.58万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9973280
关键词：
AMPA Receptors Abstinence Acute Address Affect Affective Amygdaloid structure Animals Anxiety Behavior Behavior Therapy Behavioral Brain Brain region Calcium Cell Nucleus Cessation of life Chronic Chronic stress Cognitive Complex Control Groups Coupled Data Disease Economic Burden Electrophysiology (science)Emotional Stress Exhibits Family Frequencies Functional disorder Glutamates Grant Home environment Homeostasis Kinetics Label Measures Mediating Medicine Modeling Monitor Morphine Mus Naloxone Negative Reinforcer Neurobiology Neurons Neurotransmitters Norepinephrine Occupations Opioid Opioid agonist Output Overdose Periodicity Permeability Pharmaceutical Preparations Pharmacology Pharmacotherapy Physical Dependence Physiological Physiology Population Projection Rattus Regulation Relapse Rewards Role Scanning Sex Differences Signal Transduction Sleep Sleep disturbances Societies Stress Structure of terminal stria nuclei of preoptic region Substance Withdrawal Syndrome Synapses Synaptic Transmission Synaptic plasticity Testing United States Virus Withdrawal Withdrawal Symptom addiction anxiety-like behavior comorbidity cost experience improved indexing mu opioid receptors nerve supply neural circuit neuroadaptation neuronal circuitry noradrenergic opioid abuse opioid epidemic opioid exposure opioid overdose opioid use opioid use disorder opioid withdrawal optogenetics postsynaptic presynaptic prevent receptor response sex sexual dimorphism sleep behavior transmission process uptake

项目摘要

PROJECT SUMMARY The opioid epidemic in the United States is profound, with an annual economic burden of $95.8 billion dollars (2016 dollars) and a total cost of over $1Trillion since 2001. Moreover, drug overdose is now the no. 1 cause of accidental death with over 72,000 lives lost in 2017, and opioid overdoses account for over 60% of these deaths. In order to develop pharmacological and behavioral therapies to treat opioid use disorder (OUD), it is important to understand the neural circuitry and neuroadaptation that occurs following opioid use and withdrawal. Disorders on the affective spectrum often exhibit high comorbidity. Therefore, it is imperative to understand how opioids alter critical circuits and neurotransmitters that regulate addiction-like behaviors, aversion/anxiety and the response to stress. A node in the extended amygdala, the bed nucleus of the stria terminalis (BNST), receives the densest innervation of norepinephrine (NE, a stress responsive neurotransmitter) in the brain. The BNST is a major contributor to opioid withdrawal behaviors and previously, we demonstrated that morphine exposure and withdrawal modulates BNST NE release and uptake mechanisms in rats. Our preliminary data demonstrate that chronic stress enhances the same noradrenergic circuitry mice, and that opioid exposure and withdrawal modulates NE neurons. Furthermore, in mice we observe sex specific acute withdrawal behaviors, withdrawal induced disruption of sleep rhythms, and anxiety-like behavior in protracted abstinence. The BNST is a sexually dimorphic brain region, and we observe further sex differences in (and some similarities) in BNST physiology. Intriguingly, our data suggest that there may be reductions in excitatory transmission in select circuitry following opioid withdrawal, which may ultimately alter BNST output to classical reward circuits. These data inform the central hypothesis of our proposal investigated in 3 aims: opioid withdrawal 1. enhances the synaptic drive onto NE neurons innervating the BNST, 2. facilitates enhanced noradrenergic transmission within the BNST, and 3. induces glutamatergic plasticity within the BNST intensifying opioid withdrawal syndrome related behaviors.

项目概要美国阿片类药物流行影响深远，每年造成958亿美元经济负担（2016 年美元），自 2001 年以来总成本超过 1 万亿美元。此外，药物过量现已成为头号问题。 1 原因 2017 年，意外死亡人数超过 72,000 人，其中阿片类药物过量导致死亡的人数超过 60%。为了开发治疗阿片类药物使用障碍 (OUD) 的药物和行为疗法，重要的是了解阿片类药物使用和戒断后发生的神经回路和神经适应。疾病在情感谱上的人通常表现出很高的合并症。因此，有必要了解阿片类药物如何改变调节成瘾样行为、厌恶/焦虑和对压力的反应。扩展杏仁核中的一个节点，即终纹床核 (BNST)，接收大脑中去甲肾上腺素（NE，一种压力反应性神经递质）神经支配最密集。 BNST 是是阿片类药物戒断行为的一个主要因素，之前我们证明吗啡暴露和戒断调节大鼠中 BNST NE 的释放和摄取机制。我们的初步数据表明慢性压力增强了小鼠的去甲肾上腺素能回路，并且阿片类药物暴露和戒断调节 NE 神经元。此外，在小鼠中，我们观察到性别特异性的急性戒断行为，戒断导致睡眠节律紊乱，以及长期禁欲中的焦虑样行为。 BNST 是一种性二态性大脑区域，我们观察到 BNST 生理学中进一步的性别差异（和一些相似之处）。有趣的是，我们的数据表明，以下选择电路中的兴奋性传输可能会减少阿片类药物戒断，最终可能会改变 BNST 对经典奖励回路的输出。这些数据告知我们提案的中心假设有 3 个目标：阿片类药物戒断 1. 增强突触驱动 NE 神经元支配 BNST，2. 促进 BNST 内去甲肾上腺素能传递的增强，3. 诱导 BNST 内的谷氨酸可塑性，加剧阿片类药物戒断综合征相关行为。