Nociceptin receptor signaling and regulation of dopamine transmission in drug reward circuitry

伤害感受肽受体信号传导和药物奖赏回路中多巴胺传递的调节

基本信息

批准号：
10004764
负责人：
Patrick Ross O'Neill
金额：
$ 13.55万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004764
关键词：
Advisory Committees Affect Affective Agonist Alcohols Amphetamines Arrestins Axon Biochemical Biological Assay Biology Biosensor Brain Cell membrane Cells Cocaine Corpus striatum structure Cyclic AMP Data Dendrites Dopamine Drug Addiction Drug abuse Ensure Feedback G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors GTP-Binding Proteins Genetic Goals Image Intracellular Signaling Proteins Knock-in Mouse Lead Lipids MAPK3 gene Measurement Measures Mentored Research Scientist Development Award Mentors Methods Midbrain structure Molecular Morphine Neurons Neurosciences Nucleus Accumbens ORL1 receptor Opioid Receptor Pharmacology Phosphotransferases Play Process Property Protein Isoforms Protein Kinase Protein Subunits Receptor Activation Receptor Signaling Regulation Research Research Training Resolution Rewards Rodent Role Route Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Site Sucrose System Techniques Therapeutic Time Training Universities Ventral Tegmental Area Viral Washington Work addiction behavioral response biological adaptation to stress career desensitization design dopamine transporter dopaminergic neuron drug of abuse drug reward experimental study imaging approach insight knock-down live cell imaging medical schools mutant neurotransmission new therapeutic target nociceptin optogenetics preference presynaptic protein activation protein kinase A kinase receptor receptor expression receptor-mediated signaling recruit response reward circuitry trafficking transmission process uptake

项目摘要

Project Summary The overall goal of this research is to determine how the nociceptin receptor (NOPR) modulates dopamine (DA) transmission and behavioral responses associated with drug addiction. Central administration of NOPR agonists inhibits the rewarding effects of commonly abused drugs including cocaine, morphine, amphetamine, and alcohol in conditioned place preference assays. NOPR is widely expressed in the brain, but preliminary data shows that NOPR activation in DA neurons of the ventral tegmental area (VTA) is sufficient to inhibit cocaine preference. We hypothesize that this effect is due to the demonstrated ability of NOPR activation to inhibit DA transmission to the nucleus accumbens. However, NOPR signaling has never been studied directly in midbrain DA neurons, and how it regulates DA transmission is unknown. The research objectives of this five year K01 award are: (1) to determine the intracellular signaling responses generated by NOPR activation in real-time within midbrain DA neurons, (2) to identify cellular and molecular mechanisms that control NOPR desensitization and internalization in midbrain DA neurons, and (3) to determine how NOPR signaling suppresses cocaine-induced increases in dopamine transmission. I have expertise in techniques for subcellular optogenetic manipulation and measurement of G protein coupled receptor (GPCR)-mediated signaling that make me uniquely qualified to achieve these aims. However, I require additional training in the use of primary neuronal cultures, genetic and viral methods, and for measuring dopamine uptake and dopamine transporter trafficking. My outstanding co-mentors, Drs. Michael Bruchas and N. Gautam, as well as our collaborators here at Washington University School of medicine will provide the required training. Washington University School of Medicine. Successful completion of my research and training goals, and my transition to scientific independence, will be ensured through regular interactions with my co-mentors, as well as my in-house advisory committee including Drs. Karen O'Malley, Robert Gereau, and Theodore Cicero. Overall, this Mentored Research Scientist Development Award will greatly facilitate my goal to establish myself as a leading contributor to our understanding of GPCR regulation of neurotransmission in reward and addiction circuitry.

项目摘要这项研究的总体目的是确定诺耐症治疗受体（NOPR）如何调节多巴胺（DA）与药物成瘾有关的传播和行为反应。 NOPR中央管理激动剂抑制了通常滥用药物的奖励作用，包括可卡因，吗啡，苯丙胺，在条件地点偏好分析中酒精。 NOPR在大脑中广泛表达，但初步数据表明，NOPR激活在腹侧盖区域（VTA）的DA神经元中足以抑制可卡因偏好。我们假设这种影响是由于NOPR激活的能力抑制DA向伏拟核的传播。但是，NOPR信号从未直接研究在中脑DA神经元中，及其如何调节DA传播是未知的。这五个的研究目标 K01年奖是：（1）确定NOPR激活产生的细胞内信号反应中脑DA神经元内的实时，（2）识别控制NOPR的细胞和分子机制中脑DA神经元中的脱敏和内在化，（3）确定NOPR信号如何抑制可卡因诱导的多巴胺传播的增加。我在技术方面有专业知识 G蛋白偶联受体（GPCR）介导的亚细胞光学遗传操作和测量信号使我有资格实现这些目标。但是，我需要在使用原发性神经元培养物，遗传和病毒方法，以及测量多巴胺摄取和多巴胺转运蛋白贩运。我杰出的副官员，博士。 Michael Bruchas和N. Gautam以及我们在华盛顿大学医学院的合作者将提供所需的培训。华盛顿大学医学院。成功完成了我的研究和培训目标，我过渡到科学独立性，也将通过与我的联合主张的定期互动来确保作为我的内部咨询委员会，包括Drs。 Karen O'Malley，Robert Gereau和Theodore Cicero。总体而言，这个受过指导的研究科学家发展奖将极大地促进我的目标建立自己的目标作为我们理解GPCR对神经递送的奖励和成瘾规定的主要贡献者电路。