Noradrenergic Plasticity in Opioid Withdrawal

阿片类药物戒断中的去甲肾上腺素能可塑性

• 批准号: 10380580
• 负责人: Zoe Anastasia McElligott
• 金额: $ 39.48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/10380580
• 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; Homeostasis; Job loss; Kinetics; Label; Measures; Mediating; Medicine; Modeling; Monitor; Morphine; Mus; Naloxone; Negative Reinforcer; Neurobiology; Neurons; Neurotransmitters; Norepinephrine; 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; antagonist; 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

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.

项目摘要 美国的阿片类药物流行非常深刻，年度经济负担为958亿美元 （2016年的美元），自2001年以来的总成本超过1卢比。此外，药物过量现在是第1号。 1个原因 意外死亡在2017年丧生72,000多人，阿片类药物过量占这些死亡的60％以上。 为了开发治疗阿片类药物使用障碍（OUD）的药理和行为疗法，这很重要 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 在情感频谱上通常表现出高的合并症。因此，必须了解阿片类药物如何 改变关键电路和神经递质，以调节成瘾行为，厌恶/焦虑和 对压力的反应。延长的杏仁核的一个节点，即质末端的床核（BNST）接收 大脑中去甲肾上腺素（NE，一种应激反应性神经递质）的最密度神经。 BNST是 阿片类药物戒断行为的主要贡献者，以前，我们证明了吗啡的暴露和 戒断调节大鼠的BNST NE释放和吸收机制。我们的初步数据表明 慢性应激增强了相同的去甲肾上腺素能小鼠，并且阿片类药物暴露和戒断 调节NE神经元。此外，在小鼠中，我们观察到性别特定的急性戒断行为，戒断 诱发睡眠节奏的破坏和长期节制中的焦虑行为。 BNST是性的 双态大脑区域，我们观察到BNST生理学的进一步性别差异（和一些相似之处）。 有趣的是，我们的数据表明，以下部分电路中可能会减少兴奋性传播 阿片类药物提取，最终可能将BNST输出更改为经典的奖励电路。这些数据告知 我们在3个目标中调查的提案的中心假设：阿片类药物提取1。 NE神经元支配BNST，2。促进BNST内的去甲肾上腺素能传播，3。 在BNST加强阿片类药物戒断综合征相关行为中诱导谷氨酸能的可塑性。