Does Dopamine Mediate Effects of Stress on Inhibitory Control and Smoking Lapse?

多巴胺是否介导压力对抑制控制和戒烟的影响？

• 批准号: 10646421
• 负责人: Evan D Morris
• 金额: $ 103.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646421
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Area; Behavior; Behavior Therapy; Behavioral trial; Biological; Biological Models; Brain; Brain imaging; Cigarette; Clinical Trials; Corpus striatum structure; Disinhibition; Dopamine; Dopamine Antagonists; Dorsal; Dose; Drug usage; Emotional; Endotoxins; Environment; Exhibits; Female; Functional Imaging; Functional Magnetic Resonance Imaging; Goals; Healthcare; Human; Image; Immune response; Impaired cognition; Impairment; Inflammatory Response; Interruption; Investigation; Laboratories; Lead; Link; Lipopolysaccharides; Measures; Mediating; Methods; Microglia; Modeling; Moods; Multimodal Imaging; Myalgia; Oral; Paper; Pathway interactions; Pharmaceutical Preparations; Placebos; Positron-Emission Tomography; Productivity; Publishing; Raclopride; Relapse; Research Personnel; Ritalin; Science; Signal Transduction; Smoke; Smoker; Smoking; Societies; Stress; Symptoms; TNF gene; Talents; Testing; Time; Work; acute stress; behavior test; behavioral response; brain metabolism; cigarette addiction; cigarette smoking; cognitive control; cohort; cost; dopamine system; drug relapse; efficacy evaluation; experience; experimental study; inflammatory marker; innovation; male; member; multimodality; neural; neural circuit; neural correlate; neurochemistry; neuroimaging; neuroinflammation; novel; pharmacologic; psychosocial; relapse prevention; response; smoking relapse; stressor; substance abuser; targeted treatment; therapy design; tool; transmission process

Project Summary/Abstract Impact: Addiction to cigarettes costs society $138 Billion yearly in health care consequences and lost productivity. It is very hard to quit – even for smokers who try. Conditions that make it harder for smokers to resist smoking could trigger relapse. One potential culprit is stress - which comes in many forms. But how does stress affect the brain and lead to relapse? Goals: The long-term objective of this multi-modality investigation of the links between acute stress, dopamine (DA) transmission and inhibitory control is to identify targets for therapy that will neutralize the sequela of stress and thereby prevent relapse of drug use. In the current project, we will study smokers who have been abstinent overnight to explore how a stressor may cause them to resume smoking. The immediate objective of the proposal is to test the hypothesis that striatal DA transmission mediates (serves as a link between) effects of biological stress on inhibitory control leading to relapse. Innovation: We will use a biological model of acute stress in humans, a single low dose of endotoxin (lipopolysaccharide(LPS)). For a short period, this stressor reliably elevates various markers of inflammation such as TNFα as well as sickness symptoms (e.g., muscle pain) and mild mood changes. We were the first to demonstrate with imaging that LPS triggers a cellular immune response in humans – marked by activated microglia – as well as alterations in brain metabolism. In addition, our group has introduced and validated a human laboratory model of smoking lapse behavior. We were the first to show that stress hastens reinstatement of cigarette smoking in a controlled lab environment. This project will combine both models as well as functional imaging with PET and fMRI to probe relevant neurochemistry and inhibitory circuitry. Preliminary Findings: Recently, using PET imaging, we showed that acute endotoxin enhances DA transmission in the dorsal striatum. In the human lab, we have found that LPS impairs cognitive control (essential in resisting drug relapse).These novel findings open the door to a mechanistic explanation of the connection between stress and reinstatement of drug use. Approach: We will conduct three main experiments on a cohort of male and female smokers. Experiment #1: Using PET, we will examine the effects of our stress model on DA transmission in smokers. Experiment #2: Using fMRI, we will examine the effects of our stress model on response inhibition. Experiment #3: Using our human lab paradigm, we will measure the effects of our stress model directly on smoking lapse behavior. By combing results from our three experiments, we will determine if (a) stress affects DA signaling and response inhibition in smokers, (b) DA mediates the effect of stress on disinhibition, and (c) if disinhibition predicts smoking lapse behavior.

项目摘要/摘要 影响：对香烟的成瘾，每年造成1380亿美元的医疗保健后果，损失了1380亿美元 生产率。即使对于尝试的吸烟者来说，也很难退出。使吸烟者更难的情况 抵抗吸烟可能会引发缓解。一种潜在的罪魁祸首是压力 - 有多种形式。但是如何 压力会影响大脑并导致退休吗？ 目标：这种多模式调查的长期目标是对急性压力之间联系的长期目标， 多巴胺（DA）传播和抑制性控制是确定将中和的治疗靶标 压力的后遗症，从而防止释放吸毒。在当前项目中，我们将学习吸烟者 一夜之间戒酒，以探索压力源如何导致他们恢复吸烟。直接 该提案的目的是检验纹状体DA传播介导的假设（作为链接 之间）生物压力对抑制性控制的影响导致缓解。 创新：我们将在人类中使用急性应激的生物学模型，一种低剂量的内毒素 （脂多糖（LPS））。在短时间内，这种压力源可靠地提高炎症的各种标记 例如TNFα以及疾病症状（例如肌肉疼痛）和轻度的情绪变化。我们是第一个 通过成像证明LP会触发人类的细胞免疫反应 - 以激活为标志 小胶质细胞 - 以及脑代谢的改变。此外，我们的小组介绍并验证了 人类实验室吸烟行为模型。我们是第一个表明压力加速的人 在受控的实验室环境中恢复吸烟。这个项目将将这两个模型结合在一起 以及使用PET和FMRI进行功能成像，以探测相关的神经化学和抑制作用。 初步发现：最近，使用PET成像，我们表明急性内毒素可以增强DA 在背纹状体中的传播。在人类实验室中，我们发现LP会损害认知控制 （在抵抗药物缓解的必要条件下。这些新发现为机械解释打开了大门 压力与恢复药物使用之间的联系。 方法：我们将对男性和女性吸烟者队列进行三个主要实验。实验＃1： 使用PET，我们将检查压力模型对吸烟者DA传播的影响。实验2： 使用fMRI，我们将检查压力模型对响应抑制的影响。实验＃3：使用我们的 人类实验室范式，我们将直接衡量压力模型对吸烟行为的影响。经过 梳理三个实验的结果，我们将确定（a）应力是否影响DA信号传导和响应 抑制吸烟者，（b）DA介导了压力对抑制的影响，并且（c）如果抑制预测 吸烟失误行为。