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

描述（由申请人提供）：血氧水平依赖（BOLD）功能磁共振成像（fMRI）可用于可视化药物引起的脑激活变化引起的脑局部血流动力学变化。这项提议的目的是利用这项技术来测量吸烟期间和吸烟后大脑活动的变化。很少有研究报道使用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。这些人都没有抽过烟。麦克林医院脑成像中心开发了一种磁共振（MR）兼容的吸烟装置，可用于允许同时进行MR成像的受试者吸烟。此外，已经反复证明，条件强化物，如烟的味道和气味，以及与吸烟相关的气道感觉，在尼古丁依赖个体中起着强大的强化作用。这里概述的研究旨在将这些条件强化因子与尼古丁的主要强化效应分离开来，并评估它们对BOLD fMRI信号的影响。目的：利用血氧水平依赖的功能磁共振成像来观察吸烟或安慰剂香烟以及尼古丁和生理盐水输注期间脑局部血流动力学的变化。在整个成像过程中，还将测量药物效果的主观评分。操纵尼古丁戒断状态和尼古丁依赖状态的实验将产生数据，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BOLD变化和药物效果主观评分的急性效应的影响。具体目的1：评估对吸烟反应的BOLD信号变化的时间过程和药物效应的主观评分：戒烟和依赖的影响。具体目标2：评估吸烟安慰剂烟草后BOLD信号变化的时间过程和安慰剂效应的主观评分：戒烟和依赖的影响。特定目的3：评估戒烟尼古丁依赖吸烟者静脉注射尼古丁或生理盐水后，BOLD信号变化的时间过程和对药物效果的主观评价。理论基础：以前对尼古丁影响的神经影像学研究使用了除吸烟以外的给药途径。由于吸烟提供了最快速的药物效应，并且吸烟是吸烟者使用的尼古丁管理方法（通常每天数十次），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强化物对吸烟期间大脑激活的相关影响至关重要。先前的临床和临床前研究支持戒断和依赖可能影响这种效果的观点。吸烟是可预防的主要死亡原因。尽管经过了几十年的研究，仍然没有有效的治疗烟瘾的方法。更好地了解吸烟尼古丁和安慰剂对活人大脑的影响，可能为指导合理有效的治疗方法的发展提供线索。

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.