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

项目总结/摘要 影响：吸烟成瘾每年使社会在医疗保健方面损失1380亿美元， 生产力戒烟是非常困难的-即使是吸烟者谁尝试。使吸烟者更难 抵制吸烟可能引发复发。一个潜在的罪魁祸首是压力--它有多种形式。但如何 压力会影响大脑导致复发吗？ 目标：急性应激、抑郁和抑郁之间联系的多模式研究的长期目标， 多巴胺（DA）的传输和抑制控制是确定治疗的目标， 从而防止吸毒复发。在目前的项目中，我们将研究吸烟者， 一夜之间戒烟，以探索压力如何导致他们重新吸烟。立即 该提案的目的是检验纹状体DA传递介导（作为联系）的假设， 之间）生物应激对抑制性控制的影响导致复发。 创新：我们将使用人类急性应激的生物模型，单次低剂量的内毒素 （脂多糖（LPS））。在短时间内，这种应激源可靠地提高了炎症的各种标志物 如TNFα以及疾病症状（例如，肌肉疼痛）和轻微的情绪变化。我们是第一个 通过成像证明LPS触发人体细胞免疫反应-以激活的 小胶质细胞-以及大脑代谢的改变。此外，我们的小组还推出并验证了 人类实验室吸烟行为模型。我们是第一个证明压力会加速 在受控的实验室环境中恢复吸烟。该项目将联合收割机这两种模式， 以及用PET和fMRI进行功能成像，以探测相关的神经化学和抑制回路。 初步发现：最近，我们使用PET成像显示，急性内毒素增强DA 在背侧纹状体的传输。在人类实验室中，我们发现LPS会损害认知控制， 这些新的发现打开了一扇大门，从机制上解释了 压力和药物使用恢复之间的联系。 方法：我们将对一组男性和女性吸烟者进行三项主要实验。实验1： 使用PET，我们将检查我们的压力模型对吸烟者DA传输的影响。实验2： 使用功能磁共振成像，我们将检查我们的压力模型对反应抑制的影响。实验#3：使用我们的 人类实验室范例，我们将直接测量我们的压力模型对吸烟行为的影响。通过 结合我们三个实验的结果，我们将确定（a）压力是否影响DA信号和反应 抑制吸烟者，（B）DA介导的影响，压力对去抑制，和（c）如果去抑制预测 吸烟行为

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.