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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：
10112864
负责人：
Patrick Ross O'Neill
金额：
$ 14.3万
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112864
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 conditioned place preference 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.

项目总结

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Agonist-selective NOP receptor phosphorylation correlates in vitro and in vivo and reveals differential post-activation signaling by chemically diverse agonists

DOI：
10.1126/scisignal.aau8072
发表时间：
2019-03-26
期刊：
SCIENCE SIGNALING
影响因子：
7.3
作者：
Mann, Anika;Mouledous, Lionel;Schulz, Stefan
通讯作者：
Schulz, Stefan

Chronic intermittent ethanol exposure disrupts stress-related tripartite communication to impact affect-related behavioral selection in male rats.

DOI：
10.1016/j.ynstr.2023.100539
发表时间：
2023-05
期刊：
NEUROBIOLOGY OF STRESS
影响因子：
5
作者：
Munier, J. J.;Rahal, D.;Shen, S.;Hanna, A.;Marty, V. N.;Fanselow, M. S.;Spigelman, I.;O'Neill, P. R.
通讯作者：
O'Neill, P. R.