Contribution of locus coeruleus-derived galanin to opioid reward and reinforcement

蓝斑源甘丙肽对阿片类药物奖励和强化的贡献

• 批准号: 10456900
• 负责人: DAVID WEINSHENKER
• 金额: $ 46.38万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456900
• 关键词: Acute; Adrenergic Receptor; Agonist; Anatomy; Attenuated; Behavior; Behavioral; Behavioral Symptoms; Brain; Cell Nucleus; Cells; Chronic; Complement; Data; Disinhibition; Dose; Electrophysiology (science); Frequencies; Galanin; Goals; Human; Hyperactivity; In Situ Hybridization; Knock-out; Knockout Mice; Laws; Literature; Location; Maps; Measurement; Mediating; Messenger RNA; Molecular; Morphine; Mus; Neurons; Neuropeptides; Neurotransmitters; Norepinephrine; Opiate Addiction; Opioid; Overdose; Pathway interactions; Persons; Pharmacology; Phase; Phenotype; Process; Property; Psychological reinforcement; Research; Rewards; Rodent; Self Administration; Slice; Source; Symptoms; System; Testing; Transgenic Mice; Transgenic Organisms; Ventral Tegmental Area; Wild Type Mouse; Withdrawal; Withdrawal Symptom; abuse liability; addiction; autocrine; base; combat; conditioned place preference; dopaminergic neuron; galanin receptor; gamma-Aminobutyric Acid; in vivo; locus ceruleus structure; neurochemistry; noradrenergic; novel; novel therapeutics; opioid abuse; opioid epidemic; opioid exposure; opioid therapy; opioid use; opioid withdrawal; optogenetics; overexpression; prevent; public health emergency; receptor; response; small molecule; transmission process

Project Summary The opioid epidemic has been declared a national public health emergency. Current treatments have abuse liability, target acute overdose only, and/or are ineffective for many people suffering from opioid addiction, and new therapies are desperately needed. One promising target is the brain galanin system; reducing galanin levels exacerbates morphine reward and withdrawal, while increasing galanin opposes opioid addiction-like behaviors. However, the neuroanatomical source and target of this protective galanin have not been identified, and the effects of galanin on voluntary opioid intake have not been investigated. The locus coeruleus (LC) modulates the activity of the mesolimbic reward pathway and has been implicated in opioid addiction, and 80% of noradrenergic neurons in this nucleus co-express galanin. We have assembled a set of genetically altered mice that either lack or overexpress galanin specifically in noradrenergic neurons to test the hypothesis that LC-derived galanin suppresses the ability of opioids to disinhibit dopamine (DA) neurons in the ventral tegmental area (VTA) and attenuates opioid reward/reinforcement, as well as acts in an autocrine manner to prevent LC hyperactivity and reduces withdrawal symptoms. In Aim 1, we will use in situ hybridization to determine the neurochemical identity of galanin receptor-expressing cells in the VTA, and slice and in vivo electrophysiology to investigate the circuitry and cellular mechanisms underlying the ability of galanin to oppose opioid-induced VTA DA neuron activity. In Aim 2, we will use the transgenic mice described above to test the hypothesis that LC-derived galanin inhibits opioid reinforcement using an operant i.v. opioid self- administration paradigm. In Aim 3, we will assess the ability of galanin to suppress LC hyperactivity, cellular plasticity, and aversive symptoms during opioid withdrawal. Completion of these aims will lay the groundwork for LC/galanin-based therapies for opioid addiction.

项目摘要 阿片类药物流行病已被宣布为国家公共卫生紧急事件。目前的治疗方法存在滥用 责任，仅针对急性过量，和/或对许多患有阿片类药物成瘾的人无效，以及 迫切需要新的疗法。一个有希望的目标是大脑甘丙肽系统;减少甘丙肽 水平加剧吗啡奖励和戒断，而增加甘丙肽对抗阿片类药物成瘾， 行为。然而，这种保护性甘丙肽的神经解剖学来源和靶点尚未确定， 甘丙肽对阿片类药物自愿摄入的影响尚未研究。蓝斑（LC） 调节中脑边缘奖励途径的活性，并与阿片类药物成瘾有关， 该核中80%的去甲肾上腺素能神经元共表达甘丙肽。我们已经收集了一套基因 在去甲肾上腺素能神经元中特异性地缺乏或过度表达甘丙肽的改变小鼠来验证这一假设 LC衍生的甘丙肽抑制阿片类药物解除腹侧多巴胺（DA）神经元抑制的能力， 被盖区（VTA），并减弱阿片类药物的奖励/强化，以及自分泌的方式， 防止LC活动过度，减少戒断症状。在目标1中，我们将使用原位杂交技术， 确定腹侧被盖区中甘丙肽受体表达细胞的神经化学特性，切片和体内 电生理学研究甘丙肽的能力的电路和细胞机制， 对抗阿片样物质诱导的腹侧被盖区DA神经元活动。在目标2中，我们将使用上述转基因小鼠来 使用操作性静脉注射阿片类药物自身来检验LC衍生的甘丙肽抑制阿片类药物强化的假设 管理范式在目标3中，我们将评估甘丙肽抑制LC过度活跃、细胞凋亡和细胞凋亡的能力。 可塑性和阿片类药物戒断期间的厌恶症状。这些目标的完成将为 用于基于LC/甘丙肽的阿片类药物成瘾治疗。