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: 10594470
• 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/10594470
• 关键词: AMPA Receptors; Abstinence; Accidents; 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; 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; 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; genetic approach; 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; overexpression; pharmacologic; 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.

项目总结