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: 10268173
• 负责人: DAVID WEINSHENKER
• 金额: $ 46.37万
• 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/10268173
• 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; 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; 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.

项目概要 阿片类药物流行病已被宣布为国家突发公共卫生事件。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。还原甘丙肽 水平会加剧吗啡奖赏和戒断，而增加甘丙肽则可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标尚未确定， 甘丙肽对自愿阿片类药物摄入的影响尚未进行研究。蓝斑 (LC) 调节中脑边缘奖赏通路的活动并与阿片类药物成瘾有关，并且 该核中 80% 的去甲肾上腺素能神经元共同表达甘丙肽。我们已经组装了一套基因组 对去甲肾上腺素能神经元中缺乏或过度表达甘丙肽的小鼠进行了改造，以检验这一假设 LC 衍生的甘丙肽抑制阿片类药物解除抑制腹侧多巴胺 (DA) 神经元的能力 被盖区（VTA）并减弱阿片类药物奖励/强化，以及以自分泌方式起作用 预防 LC 过度活跃并减少戒断症状。在目标 1 中，我们将使用原位杂交 确定 VTA 中甘丙肽受体表达细胞的神经化学特性，并切片和体内 电生理学研究甘丙肽能力的电路和细胞机制 对抗阿片类药物诱导的 VTA DA 神经元活性。在目标 2 中，我们将使用上述转基因小鼠 使用操作性静脉注射检验 LC 衍生的甘丙肽抑制阿片类药物强化的假设。阿片类药物自 行政范式。在目标 3 中，我们将评估甘丙肽抑制 LC 过度活跃、细胞 阿片类药物戒断期间的可塑性和厌恶症状。完成这些目标将为我们奠定基础 用于基于 LC/甘丙肽的阿片类药物成瘾疗法。