fMRI Studies Investigating the Choice Effects of Sedative/Hypnotics

描述（由申请人提供）：这是一个通过“指导研究科学家发展奖”（K01）机制获得4年资助的请求。申请人是一名行为药理学家，具有使用啮齿动物和非人灵长类动物药物滥用模型的经验，提出了一项人类临床药理学和磁共振成像培训计划。申请人的长期目标是成为一名独立的翻译研究者，熟练应用磁共振方法进行药物滥用研究。培训计划包括MR技术和实验设计的教学课程、研讨会、实验室轮换、负责开展研究的持续培训、参加药物滥用和脑成像科学会议以及与IRB和FDA的互动。该奖项的研究部分经过精心设计，与培训计划平行，旨在了解苯二氮卓类药物（BZ）作用的神经底物。对于每个培训目标，都有相应的研究指令，这将使候选人有机会实施新开发的技能。本提案中概述的实验将使用功能性磁共振成像（fMRI），以表征BZ在有药物经验的个体中诱导的药物与金钱选择效应的神经回路。第一组研究将在实验室进行，以确定口服阿普唑仑和唑吡坦的主观和选择效应的详细时间过程。第二组研究将在磁体中进行，以确定测量急性口服阿普唑仑和唑吡坦后BZ诱导的脑血流动力学反应变化的最佳参数。第三组研究将比较抗焦虑药阿普唑仑与常用助眠药唑吡坦的主观效应以及与药物与金钱选择效应相关的血流动力学反应。检查这些药物的药物诱导的大脑激活模式将导致更好地理解为什么阿普唑仑容易被滥用，而唑吡坦不是。这些研究将有助于实现该领域的总体目标，该领域一直致力于确定BZ如何介导其行为效应，以将临床有用的效应与其滥用潜力分开。

DESCRIPTION (provided by applicant): This is a request for 4 years of funding through the "Mentored Research Scientist Development Award" (K01) mechanism. The applicant, a behavioral pharmacologist with experience using rodent and nonhuman primate models of drug abuse, proposes a program of training in human clinical pharmacology and magnetic resonance imaging. The long-term goal of the applicant is to become an independent and translational investigator, skilled in the application of magnetic resonance methods for the study of substance abuse research. The training plan includes didactic coursework in MR technology and experimental design, workshops, laboratory rotations, ongoing training in the responsible conduct of research, attendance at both drug abuse and brain imaging scientific meetings, and interactions with the IRB and FDA. The research component of this award has been carefully designed to parallel the training plan and is aimed at understanding the neural substrates of benzodiazepine (BZ) action. For each training goal there is a corresponding research directive that will allow the candidate the opportunity to implement newly developed skills. The experiments outlined in this proposal will use functional magnetic resonance imaging (fMRI) in order to characterize the neural circuitry underlying the drug vs. money choice effects induced by BZs in drug-experienced individuals. The first set of studies will be undertaken in the laboratory to determine the detailed time course of the subjective and choice effects of orally administered alprazolam and zolpidem. The second set of studies will be undertaken in the magnet to determine the optimal parameters for measuring BZ-induced changes in cerebral hemodynamic response following acute oral administration of alprazolam and zolpidem. The third set of studies will compare the subjective effects, as well as the hemodynamic response associated with the drug vs. money choice effects, produced by the anxiolytic drug alprazolam to those of the popular sleep-aid zolpidem. Examining the drug-induced patterns of brain activation of these medications will lead to a better understanding of why alprazolam is readily abused, while zolpidem is not. These studies will contribute to the overarching goals of the field, which has been focused on determining how BZs mediate their behavioral effects in an effort to separate the clinically useful effects from their abuse potential.