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

项目摘要 这项研究的总体目标是确定伤害素受体(Nopr)如何调节多巴胺。 (Da)与吸毒成瘾有关的传播和行为反应。NOPR中央管理处 激动剂抑制常见滥用药物的奖赏效应，包括可卡因、吗啡、安非他明、 条件性位置偏爱分析中的酒精。NOPR在大脑中广泛表达，但初步 数据显示，腹侧被盖区(VTA)DA神经元中NOPR的激活足以抑制 对可卡因的偏好。我们假设这种效应是由于NOPR的激活被证明有能力 抑制DA向伏核的传递。然而，NOPR信号从未被直接研究过 在中脑DA神经元中，它如何调节DA传递尚不清楚。这五个方面的研究目标 K01年度奖是：(1)确定NOPR激活所产生的细胞内信号反应 实时观察中脑DA神经元，(2)识别控制NOPR的细胞和分子机制 中脑DA神经元的脱敏和内化，以及(3)确定NOPR信号如何 抑制可卡因诱导的多巴胺传递增加。我在技术方面有专业知识 G蛋白偶联受体(GPCR)介导的亚细胞光遗传操作与检测 这一信号使我唯一有资格实现这些目标。然而，我需要在以下方面进行额外培训 使用原代神经元培养、遗传和病毒方法，以及测量多巴胺摄取和 多巴胺转运体交易。我杰出的导师，迈克尔·布鲁卡斯博士和N·高坦博士，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，以及我的 向科学独立的过渡，也将通过与我的合作导师的定期互动来确保 作为我的内部顾问委员会，包括Karen O‘Malley博士、Robert Gereau博士和Theodore Cicero博士。 总体而言，这个指导性研究科学家发展奖将极大地促进我确立自己的目标 作为一位主要贡献者，我们理解了GPCR对奖赏和成瘾中神经传递的调节 电路。

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.