Psychostimulant-induced Craving and Toxicity

描述（由申请人提供）：本申请是由R提交的K02独立科学家职业发展奖的竞争性更新。克里斯托弗·皮尔斯博士这个K02职业发展计划的主要目标是让皮尔斯博士继续集中75%的精力在他的主要研究项目上。皮尔斯博士的研究目前得到了两个NIDA R01的支持，重点是可卡因渴望和成瘾的动物模型。其中一个奖项（DA15214）旨在描述可卡因诱导的药物寻求恢复的边缘系统回路，这是一种复发的动物模型。K02奖的继续将使Pierce博士能够扩大这些研究的范围，包括他的实验室先前确定的调节可卡因诱导的行为可塑性的网络中神经元活动的光遗传学调节。光遗传学是一种将光激活离子通道的病毒转染与通过光纤应用激光相结合的新兴技术。该技术允许在毫秒时间尺度上可逆地激发或抑制神经元活动。光遗传学方法提供的精确控制代表了对正在进行的药理学显微注射研究的完美补充。此外，比较和对比光遗传学操作的效果与脑深部电刺激（DBS）的效果将有助于阐明DBS的确切作用机制，这一机制尚不清楚。这些光遗传学实验将与宾夕法尼亚大学精神病学系的Olivier Berton博士合作进行。皮尔斯博士的另一个R01（DA22339）集中在多巴胺-谷氨酸相互作用的基础上的生化机制，在神经核壳的基础上恢复可卡因寻求。一个免费的方法，膜片钳电生理学，将被添加到正在进行的工作，允许检查可卡因自我管理后AMPA谷氨酸受体通道特性的变化。拟议的膜片钳实验将与宾夕法尼亚大学精神病学系的Gregory Carlson博士合作进行。在过去四年的K02资助中，从各种行政和教学责任中解脱出来的时间是非常宝贵的。K02奖的影响在2008年结出了果实，在这一点上，新成立的研究合作开始产生出版物。2008年，Pierce博士的研究小组共同撰写了两篇论文，研究AMPA受体贩运在恢复可卡因寻求中的作用，发表在Nature Neuroscience和Journal of Neuroscience上。Pierce博士的团队在2008年的《神经科学杂志》上发表了另一篇论文，重点是DBS在动物模型中减少可卡因渴望的能力。自2006年以来，皮尔斯博士的团队已经发表了17篇研究和评论文章。K02奖的延续将使Pierce博士能够保持75%的精力投入到他现有的研究中，并将促进他的研究合作的扩大（如上所述），这将对他的研究事业发展产生重大的积极影响。 公共卫生相关性：可卡因成瘾仍然是美国的一个主要公共卫生问题。本申请中描述的实验旨在描述可卡因复吸动物模型的神经元回路以及神经化学和生物化学机制。该项目的总体目标是确定可卡因渴望和成瘾的新治疗靶点。

DESCRIPTION (provided by applicant): This application is the competing renewal of a K02 Independent Scientist Career Development Award submitted by R. Christopher Pierce, Ph.D. The major goal of this K02 career development plan is to allow Dr. Pierce to continue to focus 75% effort to his primary research program. Dr. Pierce's research is currently supported by two NIDA R01s and focuses on animal models of cocaine craving and addiction. One of these awards (DA15214) aims to delineate the limbic circuitry underlying the reinstatement of cocaine-induced drug seeking, an animal model of relapse. Continuation of this K02 award will allow Dr. Pierce to expand the scope of these studies to include optogenetic modulation of neuronal activity in networks previously identified by his lab to regulate cocaine-induced behavioral plasticity. Optogenetics is an emerging technology that combines viral transfection of light-activated ion channels with laser light application via optic fiber. This technique allows for the reversible excitation or inhibition of neuronal activity on a millisecond timescale. The precise control afforded by optogenetic methods represents a perfect complement to ongoing pharmacological microinjection studies. Moreover, comparing and contrasting the effects of optogenetic manipulations to the effects of deep brain stimulation (DBS) will help illuminate the exact mechanism of action of DBS, which remains unclear. These optogenetic experiments will be performed in collaboration with Dr. Olivier Berton from the University of Pennsylvania (Penn) Psychiatry Department. Dr. Pierce's other R01 (DA22339) focuses on the biochemical mechanisms underlying dopamine-glutamate interactions in the nucleus accumbens shell that underlie the reinstatement of cocaine seeking. A complimentary methodology, patch clamp electrophysiology, will be added to ongoing work to allow for the examination of changes in AMPA glutamate receptor channel properties following cocaine self-administration. The proposed patch clamping experiments will be performed in collaboration with Dr. Gregory Carlson from the Penn Psychiatry Department. The release time from various administrative and teaching responsibilities over the past four years of K02 funding has been invaluable. The impact of the K02 award came to fruition in 2008, at which point newly formed research collaborations began to result in publications. In 2008, Dr. Pierce's research group co- authored two papers examining the role of AMPA receptor trafficking the reinstatement of cocaine seeking, which were published in Nature Neuroscience and Journal of Neuroscience. Dr. Pierce's team published another paper in Journal of Neuroscience in 2008 focusing on the ability of DBS to reduce cocaine craving in an animal model. Dr. Pierce's group has published 17 research and review articles since 2006. Continuation of this K02 award will allow Dr. Pierce to maintain 75% effort devoted to his existing research and also will facilitate the expansion of his research collaborations (as described above), which will have a significant positive impact on his research career development. PUBLIC HEALTH RELEVANCE: Cocaine addiction remains a major public health issue in the United Sates. The experiments described in this grant application are designed to delineate the neuronal circuitry as well as the neurochemical and biochemical mechanisms underlying an animal model of cocaine relapse. The overarching goal of this project is to identify novel therapeutic targets for cocaine craving and addiction.