Reinforcement-enhancing effects of NRT

描述（由申请人提供）：“NRT的强化增强作用”尼古丁显然具有初级和次级强化作用，因为尼古丁是自我给药的，与尼古丁相关的刺激（“线索”）可以成为反应的条件反射。直到最近才被忽视的是，非人类研究表明尼古丁具有第三种强化功能，即强化增强效应，或增加与尼古丁摄入无关的奖励的强化功效。值得注意的是，我们最近证明了通过吸烟摄入尼古丁的强化增强作用，这可能是人类首次，支持这些临床前研究结果的临床适用性。在两种非依赖性 和依赖性吸烟者，其他研究结果表明，依赖和戒断并不是这些尼古丁效应发生的必要条件。然而，这些效应可能只针对某些类型的奖励，特别是积极的感官奖励（视觉，听觉等）。此外，尼古丁的动力学不影响其在动物模型中的强化增强作用，与其主要和次要作用相反，但快速与逐渐摄入尼古丁本身的强化增强作用需要在人类中得到证实。尼古丁通过吸烟以外的方式，如尼古丁替代疗法（NRT），可以评估尼古丁本身对增强强化的影响，并确定其在戒烟中的临床预测价值。NRT还可以测试药代动力学是否影响这种强化增强效应，通过快速（鼻喷雾）与渐进（贴片）尼古丁摄入。研究1将检查尼古丁本身（与安慰剂相比）对60名非依赖性和依赖性吸烟者对尼古丁应答的影响，以确认我们通过吸烟获得的尼古丁结果，使用我们经过充分验证的受试者内设计来增加功效。我们假设，与安慰剂相比，NRT（贴剂或喷雾剂）后的反应会更大，表明尼古丁本身的强化增强作用，我们将探讨这些作用是否因奖励类型而异，显示特异性。研究2将确定在60名寻求永久戒烟尝试的吸烟者中，戒烟早期NRT引起的更大强化反应是否预测NRT复发的天数。我们假设，在戒烟早期，NRT引起的强化反应的增加更大，这将预示着更长的戒烟时间。这项研究非常重要，因为证明尼古丁本身在人类中的强化增强作用将对理解以下方面具有重要意义：尼古丁被忽视的强化作用可能有助于解释依赖的持续性，NRT帮助戒烟的一些功效，以及其他治疗药物或其他滥用药物的潜在类似作用。

DESCRIPTION (provided by applicant): "Reinforcement enhancing effects of NRT" Nicotine clearly has primary and secondary reinforcing effects, as nicotine is self-administered and stimuli associated with nicotine ("cues") can become conditioned reinforcers of responding. Overlooked until recently is non-human research showing that nicotine has a third reinforcing function, that of reinforcement enhancing effects, or increasing reinforcing efficacy of rewards unrelated to nicotine intake. Notably, we recently demonstrated reinforcement enhancing effects, perhaps for the first time in humans, of nicotine intake via tobacco smoking, supporting clinical applicability of these preclinical research findings. Similar effects in both nondependent and dependent smokers and other findings indicated dependence and withdrawal as not necessary for these nicotine effects to occur. Yet, these effects may be specific to only some types of reinforcers, especially positive sensory rewards (visual, auditory, etc.). Also, nicotine' kinetics do not influence its reinforcement enhancing effects in animal models, in contrast to its primary and secondary effects, but reinforcement enhancing effects of rapid versus gradual intake of nicotine per se warrants confirmation in humans. Nicotine via means other than smoking, such as nicotine replacement therapy (NRT), can assess effects of nicotine per se on enhancing reinforcement and determine its clinical predictive value in quitting smokers. NRT also can test if pharmacokinetics influences this reinforcement enhancing effect, via rapid (nasal spray) vs. gradual (patch) nicotine intake. Study 1 will examine influences of nicotine per se (versus placebo) on responding for reinforcers in 60 nondependent and dependent smokers to confirm our results with nicotine via smoking, using our well-validated within-subjects design to increase power. We hypothesize that responding will be greater after NRT (patch or spray) versus placebo, indicating reinforcement enhancing effects of nicotine per se, and we will explore whether these effects differ by type of reward, showing specificity. Study 2 will determine if greater reinforced responding due to NRT early in abstinence predicts days to relapse with NRT in 60 treatment-seeking smokers making a permanent quit attempt. We hypothesize that a greater increase in reinforced responding due to NRT early in cessation will predict longer duration of abstinence. This research is highly significant because demonstrating reinforcement enhancing effects of nicotine per se in humans would have important implications for understanding: an overlooked reinforcing effect of nicotine that may help account for persistence of dependence, some of the efficacy of NRT for aiding smoking cessation, and perhaps potentially similar actions of other therapeutic medications or other drugs of abuse.