fMRI Studies Investigating the Choice Effects of Sedative/Hypnotics

描述(申请人提供)：这是一个通过“导师研究科学家发展奖”(K01)机制提供的为期4年的资助申请。申请者是一名行为药理学家，有使用啮齿动物和非人类灵长类药物滥用模型的经验，他提出了一个人类临床药理学和磁共振成像方面的培训计划。申请者的长期目标是成为一名独立和翻译的调查员，熟练地应用磁共振方法研究药物滥用。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、负责研究进行的持续培训、出席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，以配合培训计划，旨在了解苯二氮类药物(BZ)作用的神经底物。对于每个培训目标，都有一个相应的研究指令，使应聘者有机会实施新开发的技能。这项提案中概述的实验将使用功能磁共振成像(FMRI)来表征药物与金钱选择效应背后的神经电路，这些效应由BZS在有药物经验的个人中诱导。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进程。第二组研究将在磁体中进行，以确定在急性口服阿普唑仑和唑吡坦后测量BZ引起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物阿普唑仑和广受欢迎的助眠药唑吡坦产生的主观影响，以及与药物和金钱选择影响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有助于更好地理解为什么阿普唑仑容易被滥用，而唑吡坦不容易被滥用。这些研究将有助于该领域的总体目标，该领域一直专注于确定BZS如何调节其行为影响，以努力将临床上有用的影响与其滥用潜力分开。

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.