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

药物提示反应性β-肾上腺素能调节的多样性补充：神经和行为机制

• 批准号: 10838177
• 负责人: Jason Anthony Oliver
• 金额: $ 5.71万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10838177
• 关键词: Acute; Address; Adjuvant Analgesic; Adrenergic Agents; Adrenergic Antagonists; Adrenergic beta-Antagonists; Adult; Attention; Behavioral Mechanisms; Brain region; Cessation of life; Cigarette; Cigarette Smoker; Clinical; Cues; Development; Drug Modulation; Drug usage; Exposure to; Future; Image; Intervention; Laboratories; Mediating; Modeling; Motivation; Nicotine Withdrawal; Perfusion; Pharmaceutical Preparations; Placebos; Pre-Clinical Model; Procedures; Propranolol; Protocols documentation; Research; Rest; Sampling; Scanning; Smoker; Smoking; Smoking Behavior; Smoking Cessation Intervention; Stimulus; United States; Work; addiction; behavioral response; beta-adrenergic receptor; cerebrovascular; craving; cue reactivity; design; functional MRI scan; improved; neural; neuromechanism; nicotine patch; parent grant; pharmacologic; pre-clinical; response; smoking cessation; smoking cue

PROJECT SUMMARY/ABSTRACT (FROM PARENT GRANT) 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.

项目总结/摘要（来自PAYNET GRANT） 每年有超过50%的吸烟者试图戒烟，但即使经过强化治疗， 绝大多数人会在六个月内重新吸烟。考虑到世界上每年有超过48万人死亡， 仅美国就直接归因于吸烟，因此非常需要改进吸烟 停止干预。β-肾上腺素能受体拮抗剂作为一种潜在的治疗药物已经受到了广泛的关注。 在临床前和临床模型中的成瘾治疗。传统戒烟药物 对于缓解尼古丁戒断非常有效，但对于解决 环境因素对吸烟行为的影响β-肾上腺素能药物的一个关键优势是它们靶向于 不同的机制比既定的治疗，直接遏制这些环境的影响， 吸烟动机的线索。这为辅助药物干预创造了可能性， 肾上腺素能药物与靶向尼古丁戒断的药物联合使用， 功效我们实验室最近完成的一项研究支持了这一观点，表明急性 给予普萘洛尔可减少提示诱发的烟瘾，抑制对吸烟刺激的神经反应 (e.g.香烟，打火机），并改变了关键大脑区域之间的连接，这些区域被证明可以介导预 临床模型本申请旨在通过检查β-肾上腺素能受体对细胞的影响来扩展这项工作。 在更大的样本中使用一种设计， 检查β-肾上腺素能拮抗剂单独使用和与已确定的吸烟者联合使用的效果 针对尼古丁戒断的戒烟药物。成年吸烟者（N = 80）将系统地 使用我们开发和验证的程序拍摄他们的个人吸烟环境。他们将 然后接受四次功能性磁共振成像（fMRI）扫描，在此期间，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 任一：1）尼古丁贴剂+ β-肾上腺素能拮抗剂; 2）安慰剂贴剂+ β-肾上腺素能拮抗剂; 3）尼古丁 贴剂+安慰剂药物;和4）安慰剂贴剂+安慰剂药物。分析将检查这些影响 药物对渴望和神经激活响应吸烟线索（目标1），以及神经 连通性（目标2）。此外，探索性目的将检查观察到的效应是否由以下因素介导： 静息时脑血管灌注或神经连接的变化（探索性目标3）。结果从这个 翻译项目将提供关于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提供信息， 更深入地了解可用于帮助完善未来干预方案的机制。