FMRI of cigarette smoking: Effects of dependence, withdrawal, and conditioned rei

描述(申请人提供)：血氧水平依赖(BOLD)功能磁共振成像(FMRI)可用于显示因药物引起的脑激活改变而发生的脑内局部血流动力学变化。这项建议的目的是使用这项技术来测量在吸烟和安慰剂香烟期间和之后大脑激活的变化。使用BOLD功能磁共振成像测量尼古丁或安慰剂对大脑激活的影响的研究很少有报道。这些人都没有使用过吸烟。麦克莱恩医院脑成像中心已经开发出一种与磁共振(MR)兼容的吸烟设备，该设备可用于同时进行磁共振成像的受试者吸烟。此外，已经反复证明，条件性强化物，如烟的味道和气味，以及与吸烟相关的呼吸道感觉，对尼古丁依赖者来说是强大的强化物。这里概述的研究旨在将这些条件增强剂与尼古丁的主要增强作用分开，并评估它们对BOLD功能磁共振信号的影响。目的：应用血氧水平依赖的功能磁共振成像技术，观察吸烟或安慰剂香烟以及尼古丁和生理盐水输注过程中局部脑血流动力学的变化。药物效果的主观评级也将在整个成像过程中进行测量。涉及尼古丁戒断状态和尼古丁依赖状态的实验将产生数据，这些数据将揭示这两个因素对吸烟或注射尼古丁或安慰剂对吸烟引起的大胆变化和药物效果的主观评级的急性影响。具体目标1评估对吸烟烟草反应的BOLD信号和药物效应的主观评级变化的时间进程：戒断和依赖的影响。具体目标2：评估吸烟安慰剂烟草对BOLD信号和安慰剂效果主观评分变化的时间进程：戒断和依赖的影响。具体目标3：评估静脉注射后BOLD信号和药物效果主观评分变化的时间进程。尼古丁依赖戒烟者的尼古丁或盐水输注。理论基础：以前对尼古丁影响的神经成像研究使用了吸烟以外的给药途径。由于吸烟产生的药物效应最快，而且吸烟是吸烟者使用尼古丁的方法(通常每天几十次)，因此更好地了解吸烟尼古丁的影响以及与吸烟相关的条件性增强剂对吸烟期间大脑激活的相关性的影响是至关重要的。戒断和依赖可能会影响这种效果的观点得到了先前的临床和临床前研究的支持。吸烟是主要的可预防的死亡原因。尽管有几十年的研究，但还没有有效的治疗香烟成瘾的方法。更好地了解烟熏尼古丁和安慰剂对活体人脑的影响，可能为指导合理有效的治疗方法的开发提供线索。

DESCRIPTION (provided by applicant): Blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) can be used to visualize the localized hemodynamic changes in brain which occur in response to drug-induced changes in brain activation. The objective of this proposal is to use this technique to measure changes in brain activation that occur during and after smoking tobacco and placebo cigarettes. Few studies have been reported which have measured the impact of nicotine or placebo on brain activation using BOLD fMRI. None of these have used smoked cigarettes. A magnetic resonance (MR)-compatible smoking device has been developed at McLean Hospital Brain Imaging Center that can be used to allow smoking by subjects with concurrent MR imaging. Additionally, it has been repeatedly shown that conditioned reinforcers, such as the taste and smell of smoke, as well as airway sensations associated with smoking serve as powerful reinforcers in nicotine dependent individuals. The studies outlined here are designed to separate these conditioned reinforcers from the primary reinforcing effects of nicotine, and evaluate their impact on BOLD fMRI signal. OBJECTIVE: To use blood oxygen level dependent functional magnetic resonance imaging to visualize local hemodynamic changes in brain during the smoking of tobacco or placebo cigarettes and during nicotine and saline infusion. Subjective ratings of drug effect will also be measured throughout the imaging session. Experiments involving manipulations of nicotine withdrawal status and nicotine dependence state will yield data that will reveal the impact of both these factors on the acute effects of smoked or injected nicotine or placebo on both smoking-induced BOLD changes and subjective ratings of drug effect. SPECIFIC AIM 1 Evaluate the time course of changes in BOLD signal and subjective ratings of drug effect in response to smoked tobacco: Effects of abstinence and dependence. SPECIFIC AIM 2: Evaluate the time course of changes in BOLD signal and subjective ratings of placebo effect in response to smoked placebo tobacco: Effects of abstinence and dependence. SPECIFIC AIM 3: Evaluate the time course of changes in BOLD signal and subjective ratings of drug effect in response to i.v. nicotine or saline infusion in abstinent nicotine dependent smokers. RATIONALE: Previous neuroimaging studies of the effects of nicotine have used routes of administration other than smoking. Since smoking provides the most rapid onset of drug effects and since smoking is the method of nicotine administration used by smokers (often tens of times daily), a better understanding of the effects of smoked nicotine and the impact of conditioned reinforcers associated with smoking on a correlate of brain activation during smoking is crucial. The idea that withdrawal and dependence may influence this effect is supported by previous clinical and preclinical studies. Smoking is the leading preventable cause of death. Despite decades of research, there are no effective treatments for cigarette addiction. A better understanding of the effects of smoked nicotine and placebo in living human brain may provide clues to guide development of rational and efficacious treatments.