Control of Cocaine Seeking by D1-dependent Modulation of NMDA Signaling

描述（由申请人提供）：Pavel Ortinski博士提交的五年指导职业发展奖（K 01）的当前申请建议获得药物滥用行为药理学的培训。具体而言，所要求的培训将检查D1样多巴胺和NMDA受体相互作用的可卡因自我管理和恢复可卡因寻求的动物模型中的作用。这项培训将促进 开发一个独立的研究项目，重点分析可卡因寻求和复发的突触机制。这项研究将在宾夕法尼亚大学进行，由克里斯·皮尔斯博士指导。 候选人：Ortinski博士展示了在几个实验模型中实施突触功能和生理学分析的研究项目的记录。博士学位这篇论文是在乔治敦大学完成的，由Stefano Vicini博士指导，使用细胞培养和脑切片中的电生理膜片钳记录来研究GABA-A受体亚型对抑制性突触强度的调节。Ortinski博士随后与道格拉斯库尔特博士在费城儿童医院/宾夕法尼亚大学完成了为期两年的博士后研究，在那里他评估了星形胶质细胞谷氨酸/谷氨酰胺代谢途径对癫痫患者海马网络活动抑制控制的贡献。 这些研究生和研究生的经验导致了三个第一作者的主要研究和八个共同撰写/审查出版物在同行评审期刊。为了寻找机会将他的突触生理学经验整合到更广泛的行为水平研究中，Ortinski博士与宾夕法尼亚大学医学院的Chris Pierce博士进行了一系列会议。看到可卡因滥用研究中突触功能分析的相对短缺，并意识到这代表了建立具有重大潜在影响的突触生理学研究的独立路线的机会，Ortinski博士加入了Pierce博士的实验室作为研究助理。Ortinski博士在他被任命后的短时间内，已经组装了一个从大脑切片进行电生理记录的装置，并使用它来获取（在Pierce博士的指导下）大量数据，扩展了Pierce实验室最近的一系列发现。 工作环境：宾大的基础成瘾研究社区，附属的地方中心和附近的大学是非常突出的，并创造了咨询和合作的专业知识库。在宾夕法尼亚大学充满活力的神经科学社区内的各个部门组织的会议和研讨会上有充足的科学互动机会。此外，几个校园办公室开发了博士后水平的生物医学教师的职业和研究技能培训计划。所有这些都为成功的研究和职业发展建立了广泛的资源丰富的环境。 调研：本申请中提出的研究建立在大量证据的基础上，即多巴胺和谷氨酸系统在丘脑核中的相互作用介导了药物寻求和药物服用行为的重要方面。例如，几个实验室，包括皮尔斯博士的实验室，已经证明，激活中脑核中的D1样多巴胺受体可以恢复可卡因寻求，部分原因是增加了含有GluA 1亚基的AMPA受体向该大脑区域突触的运输。然而，与整个大脑神经元可塑性的研究相反，NMDA受体参与可卡因诱导的神经元可塑性尚未得到系统的评估。我的初步研究结果表明，相对于对照动物，短暂刺激D1样多巴胺受体（可卡因自我管理过程中发生）在可卡因经验丰富的动物elyoung一个持久的增加的电流介导的NMDA受体在中型多刺神经元的核壳。已知NMDA受体参与可卡因寻求的恢复。因此，它建议，调节NMDA受体功能的D1样受体在核壳的持续可卡因寻求行为作出了重大贡献。 职业发展计划：一系列活动相结合的课程，会议和研讨会出席，正式的研究报告，动手培训和教学提出。正式的课程将包括生物统计学研究生课程的统计方法和数据分析以及神经精神药理学研究生课程。每年将参加两次研究会议：神经科学学会年会和药物依赖问题学院会议或兴奋性突触和脑功能戈登会议。每年在不同的地点提出两到三次正式的研究报告。生物医学职业技能培训将通过参加讲习班和研讨会获得。在拟议的研究过程中将获得实践培训。教学计划包括几个研究生水平的神经科学课程的讲座。职业发展计划的总体目标是促进行为药理学和神经元生理学方法在拟议的研究中的整合，并建立必要的技能基础，在成瘾研究的成功独立职业生涯。

DESCRIPTION (provided by applicant): The current application for a five-year mentored Career Development Award (K01) submitted by Dr. Pavel Ortinski proposes acquisition of training in the behavioral pharmacology of drug abuse. Specifically, the requested training will examine the role of D1-like dopamine and NMDA receptor interaction in an animal model of cocaine self-administration and reinstatement of cocaine seeking. This training will facilitate the development of an independent research program focused on the analysis of synaptic mechanisms of cocaine seeking and relapse. The research will be conducted at the University of Pennsylvania under the mentorship of Dr. Chris Pierce. Candidate: Dr. Ortinski has demonstrated a record of research projects implementing the analyses of synaptic function and physiology in several experimental models. His Ph.D. thesis, completed at Georgetown University under the mentorship of Dr. Stefano Vicini, used electrophysiological patch-clamp recordings in cell cultures and brain slices to investigate the regulation of inhibitory synaptic strength by GABA-A receptor subtypes. Dr. Ortinski then completed a two-year postdoctoral fellowship with Dr. Douglas Coulter at the Children's Hospital of Philadelphia/University of Pennsylvania where he evaluated contributions of the astrocytic glutamate/glutamine metabolic pathway to inhibitory control over hippocampal network activity in epilepsy. These graduate and post-graduate experiences resulted in three first-author primary research and eight co-authored/review publications in peer-reviewed journals. In search of opportunities to integrate his synaptic physiology experience into a broader context of behavioral-level studies, Dr. Ortinski had a series of meetings with Dr. Chris Pierce at the UPenn School of Medicine. Seeing a relative shortage of synaptic function analyses in cocaine abuse research and realizing this represented a chance to establish an independent line of synaptic physiology research with significant potential impact, Dr. Ortinski joined Dr. Pierce's laboratory as a Research Associate. In the short time since his appointment, Dr. Ortinski has assembled a set-up for electrophysiological recordings from brain slices and used it to acquire (with Dr. Pierce's guidance) a considerable amount of data extending a series of recent findings from the Pierce lab. Environment: The basic addiction research community at UPenn, affiliated local centers, and nearby universities is very prominent and creates a reservoir of expertise for consultation and collaboration. There are ample opportunities for scientific interactions at meetings and seminars organized by various departments within UPenn's vibrant neuroscience community. Additionally, several campus offices developed programs in career and research skill training for biomedical faculty at the postdoctoral level. All of these establish an extensive resource-rich environment for successful research and career development. Research: The research proposed in this application builds upon substantial evidence that interactions between dopamine and glutamate systems in the nucleus accumbens mediate important aspects of drug-seeking and drug-taking behaviors. For example, several laboratories, including that of Dr. Pierce, have demonstrated that activation of D1-like dopamine receptors in the nucleus accumbens reinstates cocaine seeking, in part, by increasing the trafficking of GluA1 subunit-containing AMPA receptors to synapses in this brain region. In contrast to studies of neuronal plasticity throughout the brain, however, the involvement of NMDA receptors in cocaine-induced neuronal plasticity has not been assessed systematically. My preliminary results show that, relative to control animals, transient stimulation of D1-like dopamine receptors (as occurs during cocaine self-administration) in cocaine-experienced animals elicits a long-lasting increase of currents mediated by NMDA receptors in the medium spiny neurons of the nucleus accumbens shell. NMDA receptors are known to be involved in reinstatement of cocaine-seeking. Thus, it is proposed that regulation of NMDA receptor function by D1-like receptors in the nucleus accumbens shell contributes significantly to persistent cocaine-seeking behaviors. Career development plan: A range of activities combining coursework, conference and workshop attendance, formal research presentations, hands-on training and teaching is proposed. Formal coursework will consist of a Statistical Methods and Data Analysis for Biostatistics graduate students course and a graduate Neuropsychopharmacology course. Two research conferences a year will be attended: an annual meeting of the Society for Neuroscience and either a meeting of the College of Problems on Drug Dependence or a Gordon conference on Excitatory Synapses and Brain Function. Two to three formal presentations of research yearly are proposed at various venues. Biomedical career skills training will be acquired through attendance of workshops and seminars. Hands-on training will be acquired in the course of the proposed research. Teaching plans include lectures in several graduate-level neuroscience courses. The overall goal of the career development plan is to facilitate the integration of behavioral pharmacology and neuronal physiology approaches in the proposed research and to establish a foundation of skills necessary for a successful independent career in addiction research.