Amphetamine-mediated CREB phosphorylation & gene express

描述：(申请人摘要) 这是一份申请NIDA指导研究事业奖(KO1)的申请，以研究 应聘者对L类钙离子通道在 苯丙胺介导的CREB磷酸化和强啡肽基因表达。 物质滥用研究的大部分进展都集中在神经细胞和 滥用药物的行为药理学。然而，直到最近， 与慢性药物使用相关的分子变化的意义在于 被拆解了。为了更好地理解大麻的成瘾特性 这些药物，应聘者将运用她的分子生物学背景进行研究 成瘾行为背后的分子机制。作为一名研究员， 候选人已经获得了分子方面的知识并接受了培训 初级纹状体多巴胺信号转导通路的机制 文化。体外研究表明，多巴胺介导的CREB具有依赖性 L类钙离子通道的磷酸化和基因表达。这是高度 与此相关的是最近发现的L类钙通道 心理刺激剂诱导的行为。通过这个奖项，候选人将 体外观察到的分子事件与体内慢性粒细胞白血病模型的相关性 安非他明，在老鼠体内。L型钙通道在苯丙胺介导的钙通道中的作用 将检测CREB的磷酸化和强啡肽基因的表达。双方都是CREB 和强啡肽直接与成瘾特性有关 精神刺激剂可卡因。候选人的培训主要是在 体外和细胞培养系统。通过这个奖项，她将进一步扩大她的 从训练到活体工作的曲目。通过这种方式接受的培训 奖项将包括学习神经解剖学、神经药理学和行为学 精神刺激性滥用的影响。特别是，候选人将在以下方面了解(1) 脑片原位杂交(2)立体定向手术介绍 药物、反义寡核苷酸和病毒载体直接进入大脑， (3)病毒载体技术--一种强有力的操纵神经元的新方法 功能，以及(4)测试运动能力。

DESCRIPTION: (Applicant's Abstract) This is a request for a NIDA Mentored Research Career Award (KO1) to study the candidate's interest in the role of L-type Ca2+ channels in amphetamine-mediated CREB phosphorylation and dynorphin gene expression. Much of the progress in substance abuse research has focused on the neuro- and behavioral pharmacology of drugs of abuse. However only recently the significance of the molecular changes associated with chronic drug use are being unraveled. Towards a better understanding of the addictive properties of these drugs, the candidate will apply her molecular biology background to study the molecular mechanisms underlying addictive behavior. As a research fellow, the candidate has gained knowledge and received training in the molecular mechanism of the dopamine signal transduction pathway in primary striatal cultures. The in vitro studies indicate a dependence of dopamine-mediated CREB phosphorylation and gene expression on L-type Ca2+ channels. This is highly relevant because of the recent implication of L-type Ca2+ channels in psychostimulant-induced behavior. Through this award the candidate will correlate the molecular events observed in vitro to an in vivo model of chronic amphetamine, in rats. The role of L-type Ca2+ channels in amphetamine-mediated CREB phosphorylation and dynorphin gene expression will be examined. Both CREB and dynorphin have been directly implicated in the addictive properties of the psychostimulant, cocaine. The candidate's training has primarily been in in vitro and cell cultures systems. Through this award she will further expand her repertoire of training to in vivo work. The training received through this award will include learning the neuroanatomy, neuropharmacology and behavioral effects of psychostimulant abuse. In particular the candidate will learn (1) in situ hybridization in brain slices (2) stereotaxic surgeries to introduce drugs, antisense oligonucleotides and viral vectors directly into the brain, (3) viral vector technology, a powerful new method to manipulate neuronal function, and (4) test locomotor activity.