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

• 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
• 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

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 这项研究的总体目标是确定伤害感受素受体（NOPR）如何调节多巴胺 (DA)与药物成瘾有关的传播和行为反应。国家公共行政办公室的中央管理 激动剂抑制通常滥用的药物包括可卡因，吗啡，安非他明， 和酒精的影响。NOPR在大脑中广泛表达，但初步 数据显示，腹侧被盖区（VTA）的DA神经元中的NOPR激活足以抑制 可卡因偏好我们假设这种效应是由于NOPR激活的能力， 抑制DA向丘脑核的传递。然而，NOPR信号转导从未被直接研究过 在中脑DA神经元，以及它如何调节DA传输是未知的。这五项研究的目的 今年K01奖是：（1）确定细胞内信号反应所产生的NOPR激活， 实时在中脑DA神经元，（2）以确定控制NOPR的细胞和分子机制 在中脑DA神经元的脱敏和内化，和（3）以确定如何NOPR信号转导 抑制可卡因引起的多巴胺传递增加。我在技术方面很有经验 G蛋白偶联受体（GPCR）介导的亚细胞光遗传学操作和测量 这表明我有能力实现这些目标。但是，我需要额外的培训， 使用原代神经元培养物、遗传和病毒方法，以及测量多巴胺摄入和 多巴胺转运蛋白运输我杰出的共同导师，迈克尔·布鲁查斯博士和N。高塔姆，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。成功完成我的研究和培训目标， 过渡到科学独立，将通过与我的共同导师定期互动，以及 作为我的内部顾问委员会，包括卡伦·奥马利博士、罗伯特·格罗博士和西奥多·西塞罗博士。 总的来说，这个指导研究科学家发展奖将大大促进我的目标，建立自己 作为我们理解GPCR调节奖赏和成瘾中神经传递的主要贡献者 电路