Reinforcement-enhancing effects of nicotine

描述（由申请人提供）：“尼古丁的增强作用”尼古丁在人类和动物模型中明显具有原发性和继发性增强作用。最近对啮齿动物的研究表明，尼古丁可能还有第三种强化功能；强化强化效应，或增加与尼古丁摄入无关的奖励的强化效果。这项R21申请旨在确定尼古丁是否通过吸烟对人体有强化增强作用。100名吸烟者，50名尼古丁依赖者和50名非尼古丁依赖者，将参加4个实验阶段，包括：1)吸烟尼古丁（0.6毫克）香烟或2)吸烟denic（0.05毫克）香烟或3)不吸烟，每个人都在一夜戒烟后，或4)在没有一夜戒烟后吸烟自己的品牌（探索性条件）。在每一个阶段，他们将对一项简单的操作性任务做出反应，目的是获得少量的钱，短暂地播放喜欢的音乐，避免令人厌恶的白噪音，或者没有奖励（对照组）。我们的主要具体目的是检查尼古丁通过吸烟对奖励反应的影响。我们假设，与不吸烟相比，吸烟后的强化反应会更大，这表明尼古丁本身具有强化增强作用。尼古丁对某些奖励与其他奖励或无奖励的反应的影响表明，尼古丁对某些奖励的强化增强是特定的，而不是尼古丁摄入的普遍效应。正如在啮齿动物研究中观察到的那样，尼古丁对非依赖吸烟者和依赖吸烟者的强化增强效应表明，这些效应不需要建立依赖，而是反映了强化的绝对增强。大量的试点工作支持了项目的可行性，并指出了这些假设结果的可能性。相比之下，如果仅在依赖而非非依赖吸烟者中观察到效果，则可能反映了戒断缓解，而不是真正的强化增强。第二个目的是探索尼古丁增强作用的性别差异。这项研究非常重要，因为证明尼古丁对人类的强化增强作用将对我们理解尼古丁依赖具有非常重要的意义。这将表明，吸烟不仅“仅仅”从尼古丁的直接精神作用中提供强化，而且在吸烟者的环境中，更广泛地增加了其他奖励的强化作用。因此，戒烟除了失去尼古丁的精神作用外，还会导致这种广泛强化的丧失。这种广泛的强化损失可以通过吸一根烟（即一段时间）来恢复，这有助于解释吸烟行为的持久性。研究结果将为改善戒烟治疗提供指导。这份R21报告符合PA-10-069“NIH探索性发展研究资助计划”的要求。

DESCRIPTION (provided by applicant): "Reinforcement-enhancing effects of nicotine" Nicotine clearly has primary and secondary reinforcing effects in humans and animal models. Very recent research in rodents indicates that nicotine may also have a third reinforcing function; that of reinforcement-enhancing effects, or increasing the reinforcing efficacy of rewards unrelated to nicotine intake. This R21 application seeks to determine whether nicotine via smoking has reinforcement enhancing effects in humans. One hundred smokers, 50 nicotine dependent and 50 nondependent, will participate in 4 experimental sessions, involving: 1) smoking nicotine (0.6 mg) cigarettes or 2) smoking denic (0.05 mg) cigarettes or 3) no smoking, each after overnight abstinence, or 4) smoking their own brand after no overnight abstinence (exploratory condition). In each session, they will respond on a simple operant task for small amounts of money, brief access to preferred music, avoidance of aversive white noise, or no reward (control). Our primary specific aim is to examine the influence of nicotine via smoking on responding for rewards. We hypothesize that reinforced responding will be greater after smoking a nicotine vs a denic cigarette (and vs. no smoking), indicating reinforcement enhancing effects of nicotine per se. Effects of nicotine on responding for some rewards versus others or no reward will indicate that reinforcement enhancement due to nicotine is specific to certain rewards and not a generalized effect of nicotine intake. Reinforcement-enhancing effects of nicotine in nondependent smokers, as well as dependent smokers, would suggest that these effects do not require the establishment of dependence and reflect absolute enhancement of reinforcement, as observed in the rodent studies. Substantial pilot work supports project feasibility and points to the likelihood of these hypothesized results. By contrast, if effects are observed only in dependent and not nondependent smokers, they could reflect withdrawal relief and not true enhancement of reinforcement. A secondary aim is to explore sex differences in the reinforcement enhancing effects of nicotine. This research is highly significant because demonstrating reinforcement-enhancing effects of nicotine in humans would have very important implications for our understanding of nicotine dependence. It would indicate that smoking does not "just" provide reinforcement from direct psychoactive effects of nicotine but rather broadly increases the reinforcing effects of the other rewards in a smoker's environment. Therefore, quitting smoking would result in a loss of this broad reinforcement, in addition to loss of nicotine's psychoactive effects. This broad reinforcement loss could be restored by smoking one cigarette (i.e. a lapse), helping to explain the persistence of smoking behavior. Results would provide directions for improving cessation treatments. This R21 submission fits the requirements of PA-10-069, "NIH Exploratory Developmental Research Grant Program." PUBLIC HEALTH RELEVANCE: "Reinforcement enhancing effects of nicotine" This project will determine whether nicotine via cigarette smoking increases the reinforcing value of other rewards unrelated to smoking, as indicated by recent rodent studies. Dependent and nondependent smokers will work on a computer task to earn various small rewards after smoking nicotine or denic cigarettes or not smoking. This research is highly significant because demonstrating reinforcement-enhancing effects of nicotine in humans would have very important implications for our understanding of nicotine dependence. It would indicate that smoking does not "just" provide reinforcement from direct psychoactive effects of nicotine, but rather broadly increases the reinforcing effects of the other rewards in a smoker's environment. Therefore, quitting smoking could result in a loss of this broad reinforcement, in addition to loss of nicotine's psychoactive effects. This broad reinforcement loss could be restored by smoking a cigarette (i.e. a lapse), helping to explain why a lapse almost invariably leads to relapse after a quit attempt.