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

基本信息

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
项目类别：
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

项目摘要

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已被宣布为全国公共卫生紧急情况。当前的治疗遭到虐待责任，目标急性过量和/或对许多患有阿片类药物成瘾的人无效，并且迫切需要新的疗法。一个有前途的目标是脑甘氨酸系统。减少加拉宁等级加剧吗啡奖励和戒断，而加拉宁增加了类似阿片类药物的成瘾行为。然而，尚未确定这种保护性加拉宁的神经解剖来源和靶标尚未研究Galanin对自愿摄入量的影响。基因座（LC）调节中唇奖励途径的活动，并与阿片类药物成瘾有关，并该原子核共表达甘岩的80％的去甲肾上腺素能神经元。我们已经组装了一组遗传改变了在去甲肾上腺素能神经元中缺乏或过表达galanin以检验假设的小鼠 LC衍生的Galanin抑制了阿片类药物在腹侧抑制多巴胺（DA）神经元的能力对段区域（VTA）并减轻阿片类药物的奖励/增强，并以自分泌方式行事预防LC多动症并减少戒断症状。在AIM 1中，我们将使用原位杂交来确定VTA中表达甘丙蛋白受体的细胞的神经化学认同，并切成薄片和体内电生理学，以研究加拉宁能力的基础电路和细胞机制反对阿片类药物诱导的VTA DA神经元活性。在AIM 2中，我们将使用上面描述的转基因小鼠检验以下假设：LC衍生的Galanin使用手术i.v.阿片类型自我管理范式。在AIM 3中，我们将评估Galanin抑制LC多动，细胞的能力在阿片类药物戒断期间的可塑性和厌恶症状。这些目标的完成将奠定基础用于基于LC/Galanin的阿片类药物成瘾疗法。