Psychostimulant-induced Craving and Toxicity

描述(由申请人提供)：本申请书是R.Christopher Piells博士提交的K02独立科学家职业发展奖的竞争性续展。该K02职业发展计划的主要目标是允许Piels博士继续将75%的精力集中在他的主要研究计划上。皮尔斯博士的研究目前得到了两个NIDA R01的支持，并专注于可卡因渴求和成瘾的动物模型。其中一个奖项(DA15214)旨在描绘恢复可卡因诱导的药物寻找的边缘回路，这是一种复发的动物模型。这项K02奖的延续将使皮尔斯博士能够扩大这些研究的范围，包括他的实验室以前发现的调节可卡因诱导的行为可塑性的网络中神经活动的光遗传调节。光遗传学是一项新兴的技术，它将光激活离子通道的病毒导入与通过光纤的激光应用相结合。这项技术允许在毫秒的时间尺度上可逆地兴奋或抑制神经元的活动。光遗传方法提供的精确控制是对正在进行的药物微注射研究的完美补充。此外，将光遗传操作的效果与脑深部刺激(DBS)的效果进行比较和对比将有助于阐明DBS的确切作用机制，目前尚不清楚。这些光遗传学实验将与宾夕法尼亚大学(宾夕法尼亚大学)精神病学系的奥利维尔·伯顿博士合作进行。皮尔斯博士的另一篇R01(DA22339)专注于伏隔核壳内多巴胺-谷氨酸相互作用的生化机制，这些机制是恢复寻找可卡因的基础。一种免费的方法学，膜片钳电生理学，将被添加到正在进行的工作中，以允许检查AMPA谷氨酸受体通道特性在可卡因自我给药后的变化。拟议的膜片钳实验将与宾夕法尼亚大学精神病学系的格雷戈里·卡尔森博士合作进行。在过去的四年里，K02基金从各种行政和教学责任中解脱出来的时间是无价的。K02奖的影响在2008年取得成果，在这一点上，新形成的研究合作开始导致出版。2008年，皮尔斯博士的研究小组与人合著了两篇论文，考察了AMPA受体贩运在恢复寻找可卡因方面的作用，并发表在《自然神经科学》和《神经科学杂志》上。2008年，皮尔斯博士的团队在《神经科学杂志》上发表了另一篇论文，重点研究了DBS在动物模型中降低可卡因欲望的能力。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。延续这一K02奖项将使皮尔斯博士能够将75%的精力投入到他现有的研究中，并将有助于扩大他的研究合作(如上所述)，这将对他的研究事业发展产生重大的积极影响。

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.