Reinforcement-enhancing effects of nicotine

描述(由申请人提供)：“尼古丁的强化效应”尼古丁显然在人类和动物模型中具有主要和次要的强化效应。最近对啮齿动物的研究表明，尼古丁还可能具有第三种强化功能；即增强强化效果，或增加与尼古丁摄入量无关的奖励的强化效果。这个R21应用程序试图确定吸烟中的尼古丁是否对人体有增强作用。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次实验，涉及：1)吸烟(0.6毫克)香烟或2)吸烟(0.05毫克)香烟或3)不吸烟，每次戒烟一夜，或4)不彻夜戒烟(探索性条件)后抽自己的品牌。在每节课中，他们会对一项简单的操作任务做出反应，以换取少量的钱，短暂地接触喜欢的音乐，避免令人厌恶的白噪音，或者没有奖励(控制)。我们的主要目标是研究尼古丁通过吸烟对奖赏反应的影响。我们假设，在吸食尼古丁后，增强的反应将比吸食非尼古丁香烟(以及与不吸烟相比)更强，这表明强化增强尼古丁本身的效果。尼古丁对某些奖赏与其他奖赏或没有奖赏的反应的效果表明，尼古丁的强化增强是特定奖赏所特有的，而不是尼古丁摄入量的普遍影响。尼古丁在非依赖吸烟者和依赖吸烟者中的强化作用表明，这些效应不需要建立依赖，反映了啮齿动物研究中观察到的强化的绝对增强。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，如果只在依赖吸烟者中观察到效果，而不是非依赖吸烟者，它们可能反映了戒烟缓解，而不是真正的强化。第二个目的是探索尼古丁强化效果的性别差异。这项研究意义重大，因为证明尼古丁对人类的强化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，吸烟不只是从尼古丁的直接精神作用中提供强化，而是广泛地增加吸烟者所处环境中其他奖励的强化效果。因此，除了尼古丁的精神活性作用外，戒烟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抽一支烟(即一次失误)来恢复，这有助于解释吸烟行为的持久性。研究结果将为改进戒烟治疗提供指导。这份R21文件符合PA-10-069《美国国立卫生研究院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."