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

药物提示反应性的β-肾上腺素调节：神经和行为机制

• 批准号: 10618895
• 负责人: Jason Anthony Oliver
• 金额: $ 48.87万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618895
• 关键词: Acute; Address; Adjuvant Analgesic; Adjuvant Therapy; Adrenergic Agents; Adrenergic Antagonists; Adrenergic beta-Antagonists; Adult; Amygdaloid structure; Attention; Attenuated; Automobile Driving; Award; Basic Science; Behavior; Behavioral; Behavioral Mechanisms; Brain; Brain region; Cerebrovascular Circulation; Cessation of life; Cigarette; Cigarette Smoker; Clinical; Clinical Research; Crossover Design; Cues; Development; Drug Modulation; Drug Targeting; Drug usage; Emotional; Exposure to; Follow-Up Studies; Future; Goals; Health Personnel; Hippocampus; Hour; Human; Image; Impairment; Intervention; Laboratories; Medial; Mediating; Mediation; Memory; Methods; Modeling; Motivation; National Institute of Drug Abuse; Nicotine Withdrawal; Participant; Pathway interactions; Pattern; Perfusion; Pharmaceutical Preparations; Placebos; Play; Policy Maker; Pre-Clinical Model; Prefrontal Cortex; Procedures; Propranolol; Protocols documentation; Psychological reinforcement; Public Health; Relapse; Research; Research Personnel; Rest; Retrieval; Rodent Model; Role; Sampling; Scanning; Scientist; Series; Shapes; Smoker; Smoking; Smoking Behavior; Smoking Cessation Intervention; Stimulus; System; Testing; Translational Research; United States; Withdrawal Symptom; Work; addiction; behavioral response; beta-adrenergic receptor; cerebrovascular; cigarette smoking; cognitive control; cognitive process; craving; cue reactivity; design; drug development; functional MRI scan; imaging science; improved; neural; neurobiological mechanism; neuroimaging; neuromechanism; nicotine patch; pharmacologic; pill; pre-clinical; preclinical study; preference; programs; response; smoking abstinence; smoking cessation; smoking cue; therapy development

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.

项目摘要/摘要 超过50％的吸烟者每年都试图戒烟，但即使接受密集治疗， 绝大多数将在六个月内恢复吸烟。每年有超过480,000人死亡 仅美国直接归因于吸烟，需要改善吸烟 停止干预措施。 β-肾上腺素能接收器拮抗剂已受到了极大的关注 在临床前和临床模型中均进行成瘾的治疗。传统的戒烟药 对于减轻尼古丁的戒断非常有效，但在解决的影响方面有效得多 关于吸烟行为的环境线索。 β-肾上腺素药物的一个关键优点是它们靶向 与已建立的治疗不同的机制，直接遏制这些环境的影响 提示吸烟动机。这为可调节药物干预措施创造了潜力，从而β- 肾上腺药物与靶向尼古丁提取的药物结合使用，以最大程度地发挥潜力 最近在我们的实验室完成的研究支持了这一想法，表明急性 普萘洛尔的给药减少了提示发动的渴望，抑制了对吸烟刺激的中性反应 （例如，香烟，打火机），并改变了关键大脑区域之间的连通性 临床模型。该应用程序通过检查β-肾上腺素的影响来扩展这项工作 使用启用的设计，在较大样本中对吸烟提示的神经元和行为反应的药物 检查单独检查β-肾上腺素拮抗剂的作用，并结合既定的吸烟 靶向尼古丁提取的戒烟药物。成人吸烟者（n = 80）将系统地 摄影师使用我们已经开发和验证的程序的个人吸烟环境。他们会的 然后进行四个功能性磁共振成像（fMRI）扫描，在此期间它们将暴露于 吸烟刺激，包括其个人吸烟环境的图像。在每次扫描之前，他们都会收到 两者：1）尼古丁斑块 +β-肾上腺素能拮抗剂； 2）安慰剂斑块 +β-肾上腺素能拮抗剂； 3）尼古丁 补丁 +安慰剂药物； 4）安慰剂补丁 +安慰剂药物。分析将检查这些影响 响应吸烟线索的渴望和神经激活的药物（AIM 1）以及神经元 连接性（AIM 2）。此外，探索目的将检查观察到的效果是否由 休息时脑血管灌注或神经连通性的变化（探索性目的3）。结果 翻译项​​目将提供有关β-肾上腺素能药物神经基础的有价值信息。 它将直接告知开发新的药物剂，以戒烟和 提供对可用于帮助完善未来干预方案的机制的更深入的理解。