Beta-Adrenergic Modulation of Drug Cue Reactivity: Neural and Behavioral Mechanisms

项目摘要/摘要 每年有超过50%的吸烟者试图戒烟，但即使经过强化治疗， 绝大多数人将在六个月内重新吸烟。由于每年有超过48万人死于 仅美国一国就直接归因于吸烟，因此迫切需要改善吸烟状况 戒烟干预。β-肾上腺素能受体拮抗剂作为一种潜在的 在临床前和临床模式中治疗成瘾。传统戒烟药物 对缓解尼古丁戒断非常有效，但在解决以下问题上效果要差得多 吸烟行为的环境线索。β肾上腺素能药物的一个关键优势是它们针对的是 不同于既定治疗的机制，直接抑制这些环境的影响 关于吸烟动机的线索。这为辅助药物干预创造了可能性，从而使β- 肾上腺素能药物与针对尼古丁戒断的药物联合使用，以最大限度地发挥潜力 功效。我们实验室最近完成的一项研究支持这一观点，表明急性 心得安可减少线索诱发的渴求，抑制对吸烟刺激的神经反应 (如香烟、打火机)，并改变大脑关键区域之间的连通性，显示出在预激反应中起中介作用 临床模型。本申请试图通过检查β-肾上腺素能的影响来扩展这项工作 在更大样本中使用药物对吸烟线索的神经和行为反应的影响 β-肾上腺素能拮抗剂单独及与已建立的吸烟联合作用的研究 以尼古丁戒断为目标的戒断药物。成年吸烟者(N=80)将系统性地 使用我们开发和验证的程序拍摄他们的个人吸烟情况。他们会 然后接受四次功能磁共振成像(FMRI)扫描，在扫描期间，他们将暴露于 吸烟刺激，包括他们个人吸烟环境的图像。在每次扫描之前，他们将收到 1)尼古丁贴片+β-肾上腺素能拮抗剂；2)安慰剂贴片+β-肾上腺素能拮抗剂；3)尼古丁 贴片+安慰剂药物；以及4)安慰剂贴片+安慰剂药物。分析将考察这些因素的影响 对吸烟线索反应的渴求和神经激活的药物(目标1)，以及神经 连通性(目标2)。此外，一个探索性的目标将检查观察到的影响是否由 静息状态下脑血管灌注或神经连接的变化(探索性目标3)。由此产生的结果 翻译项目将提供有关β肾上腺素能药物的神经基础的有价值的信息。 它将直接为开发一种新的戒烟药物和药物提供信息。 加深对可用于完善未来干预方案的机制的理解。

PROJECT SUMMARY/ABSTRACT More than 50% of smokers attempt to quit smoking each year, but even with intensive treatment the overwhelming majority will return to smoking within six months. Given over 480,000 deaths each year in the United States alone are directly attributable to smoking, there is a tremendous need for improved smoking cessation interventions. β-adrenergic receptor antagonists have received substantial attention as a potential treatment for addiction across both pre-clinical and clinical models. Traditional smoking cessation medications are very effective for alleviating nicotine withdrawal but much less effective at addressing the influence of environmental cues on smoking behavior. One key advantage of β-adrenergic drugs is that they target a different mechanism than established treatments, acting to directly curb the influence of these environmental cues on smoking motivation. This creates the potential for adjuvant medication interventions, whereby β- adrenergic drugs are used in combination with medications targeting nicotine withdrawal to maximize potential efficacy. A recently completed study in our laboratory supports this idea, demonstrating that acute administration of propranolol reduces cue-provoked craving, suppresses neural response to smoking stimuli (e.g. cigarettes, lighters), and alters connectivity between key brain regions shown to mediate effects in pre- clinical models. This application seeks to expand upon this work by examining the impact of β-adrenergic drugs on neural and behavioral response to smoking cues in a larger sample using a design that enables examination of the effects of a β-adrenergic antagonist alone and in combination with an established smoking cessation medication targeting nicotine withdrawal. Adult cigarette smokers (N = 80) will systematically photograph their personal smoking contexts using procedures we have developed and validated. They will then undergo four functional magnetic resonance imaging (fMRI) scans during which they will be exposed to smoking stimuli, including images of their personal smoking contexts. Prior to each scan, they will receive either: 1) Nicotine Patch + β-Adrenergic Antagonist; 2) Placebo Patch + β-Adrenergic Antagonist; 3) Nicotine Patch + Placebo Drug; and 4) Placebo Patch + Placebo Drug. Analyses will examine the effects of these medications on craving and neural activation in response to smoking cues (Aim 1), as well as neural connectivity (Aim 2). In addition, an exploratory aim will examine whether observed effects are mediated by changes in cerebrovascular perfusion or neural connectivity at rest (Exploratory Aim 3). Results from this translational project will provide valuable information on the neural underpinnings of β-adrenergic medications. It will directly inform the development of a new line of pharmacological agents for smoking cessation and provide a deeper understanding of mechanisms that can be used to help refine future intervention protocols.