Neurobehavioral substrates of propranolol's effects on drug cue reactivity

项目总结/摘要 越来越多的临床前文献表明，β-肾上腺素能拮抗剂药物可能对 治疗毒瘾研究表明，这些药物的管理可以减少偏好， 通过联想学习范式与药物滥用相关的环境（即条件场所 优先权），并防止在灭绝后恢复。虽然这些神经机制 在啮齿动物模型中仔细检查了这些影响，很少有研究检查了神经行为 普萘洛尔对人类药物使用刺激反应的影响。我们实验室最近的一项研究表明， 暴露于个人吸毒环境的图像激活了与吸毒相关的大脑区域。 啮齿动物模型中条件性位置偏爱的表达。This Imaging -科学追踪奖 研究过渡（I/START）赠款将扩大这项工作，以检查普萘洛尔对神经和 人类吸烟者对药物使用环境的行为反应。该项目的总体目标是 阐明普萘洛尔可能对人类吸烟行为产生影响的脑机制 并获得关于其潜在临床用途的初步数据。40名成年吸烟者将识别并 拍摄与吸烟有关的环境和与禁欲有关的环境， 这是我们开发并验证过的程序然后他们将被随机分配到 普萘洛尔（40 mg）或安慰剂，然后立即进行功能性磁共振成像 （fMRI）扫描。在扫描过程中，他们将看到他们以前的个性化吸烟环境的图像。 照片，以及标准吸烟环境和近端吸烟线索（例如打火机，烟灰缸）。 扫描后，参与者将立即完成一项实验室任务，测试他们的抵抗能力， 吸烟以换取金钱奖励，同时暴露于个性化的吸烟环境 继续。我们假设普萘洛尔会减弱个人吸烟引起的大脑激活 在先前研究中确定的几个目标大脑区域的环境中， 在这些地区（即功能连接），并增加抵制吸烟的意愿，以换取 货币激励。额外的探索性分析将检查神经元之间的关系。 激活/连接和吸烟冲动/行为。这项I/START赠款的结果将为一个 随后的R 01应用程序，研究普萘洛尔和类似药物的神经机制， 大规模试验的背景下。因此，本研究具有很强的翻译潜力。它将提供 关于β肾上腺素能药物对以下反应的神经基础的有价值的信息： 药物使用环境及其与吸烟行为的关系。它还将为发展和研究提供信息， 它们都是用于吸烟和其它成瘾的新的和已建立的药理学治疗。

PROJECT SUMMARY/ABSTRACT A growing body of pre-clinical literature suggests beta-adrenergic antagonist medications may be effective for treating addiction. Studies show that administration of these medications can reduce preference for environments associated with drugs of abuse via associative learning paradigms (i.e. conditioned place preference) and protect against reinstatement following extinction. Although the neural mechanisms of these effects have been carefully examined in rodent models, very little research has examined the neurobehavioral effects of propranolol on responses to drug use stimuli in humans. A recent study in our laboratory indicated that exposure to images of personal drug-use contexts activates the same brain regions involved in the expression of conditioned place preference in rodent models. This Imaging – Science Track Award for Research Transition (I/START) grant will extend that work to examine the effects of propranolol on neural and behavioral responses to drug-use contexts in human smokers. The overarching goal of this project is to elucidate the brain mechanisms through which propranolol may exert an effect on human smoking behavior and to obtain preliminary data regarding its potential clinical use. Forty adult smokers will identify and photograph environments they associate with smoking and environments they associate with abstinence using a procedure we have developed and validated. They will then be randomly assigned to receive either propranolol (40-mg) or placebo immediately prior to undergoing a functional magnetic resonance imaging (fMRI) scan. During the scan, they will view images of the personalized smoking environments they previously photographed, as well as standard smoking environments and proximal smoking cues (e.g. lighters, ashtrays). Immediately following the scan, participants will complete a laboratory task that assays their ability to resist smoking in exchange for monetary incentives while exposure to personalized smoking environments continues. We hypothesize that propranolol will attenuate brain activations in response to personal smoking environments across several target brain regions identified in prior research, reduce covariation of activations across these regions (i.e. functional connectivity) and increase willingness to resist smoking in exchange for monetary incentives. Additional exploratory analyses will examine the relationship between neural activation/connectivity and smoking urge/behavior. Results of this I/START grant will provide support for a subsequent R01 application investigating the neural mechanisms of propranolol and similar medications in the context of larger-scale trials. Accordingly, this research has strong potential for translation. It will provide valuable information on the neural underpinnings of the effects of beta adrenergic medications on responses to drug-use contexts and their relationship with smoking behavior. It will also inform the development and study of both novel and established pharmacological treatments for cigarette smoking and other addictions.