Understanding and mitigating exacerbated nicotine use resulting from Pavlovianinteroceptive conditioning

项目摘要 尼古丁是烟草中的主要成瘾成分。对于个人来说，长期吸烟与以下因素有关： 心脏病和多种癌症的发病率显著上升。越来越多的研究人员正在记录 与含有尼古丁的电子烟调味汁相关的健康问题。有一些重要的性 慢性尼古丁使用的差异及其健康后果。平均而言，女性受到的影响更大 环境和社会文化因素，需要更少的时间成为尼古丁依赖，使更少的尝试， 戒烟、戒断时间较短、复发率较高，尼古丁替代疗法获益较少。巨大 对个人和社会的益处将来自于对促成这些变化的因素的更全面的理解。 尼古丁的使用和滥用通过巴甫洛夫条件反射过程，环境刺激与 诸如尼古丁之类的药物可以成为寻求药物行为的强有力的调节剂。另一个相关和 慢性尼古丁使用发展的一个重要因素是尼古丁的药理作用， 一种与其他刺激物（例如，对等 接受，酒精，工作休息，缓解压力等）。因此，吸烟者/vapers随着时间的推移， 尼古丁的刺激作用。我们的长期目标是了解 调节历史改变了个体使用和滥用的轨迹，并在这样做的过程中，提供了新的线索， 如何改进戒烟计划为此，我们最近开发了一种创新的新方法， 它将静脉内（IV）尼古丁的内感受性调节与其随后的自我给药相结合。当IV 尼古丁反复与食欲增强剂配对（即，蔗糖），这种调节史剂量-和性别- 依赖性地增加尼古丁自我给药（21%至126%）-在雌性大鼠中的作用更明显。 利用这一新方法的方法优势，我们在本提案中提出三个目标。 目标1将评估是否需要回忆的学习后，保留间隔改变的强度， 尼古丁的条件强化作用。目标2将决定在生产过程中加入弱吸收剂 自我给药与尼古丁及其新获得的条件强化作用相互作用。目标3将 检查外部（外感受性）刺激是否会与内感受性尼古丁刺激竞争， 条件强化值，从而削弱其对尼古丁摄入量的后期影响。的基本理解 影响尼古丁内感受性条件反射效果的这些因素将改进和推进我们的研究。 理论模型。这些进展将为其他基础科学家提供基础研究和线索 临床科学家和医疗保健提供者致力于改善治疗尼古丁使用障碍的方法。

PROJECT ABSTRACT Nicotine is the primary addictive constituent in tobacco. For an individual, chronic tobacco use is associated with a significant increase in heart disease and many forms of cancer. Increasingly, researchers are documenting health issues associated with vaping flavored e-juice containing nicotine. There are some important sex differences in chronic nicotine use and its health consequences. Women on average are impacted more by environmental and sociocultural factors, take less time to become nicotine dependent, make fewer attempts to quit, abstain for less time, relapse at higher rates, and benefit less from nicotine replacement therapy. Enormous gains to the individual and society would come from a more complete understanding of factors that contribute to nicotine use and misuse. Through Pavlovian conditioning processes, environmental stimuli associated with drugs such as nicotine can become powerful modulators of drug-seeking behavior. Another related and important factor in the development of chronic nicotine use is the pharmacological effects of nicotine serving as an internal (interoceptive) stimulus that enters into a conditioned association with other reinforcers (e.g., peer acceptance, alcohol, work breaks, stress relief, etc.). Thus, smokers/vapers over time develop a rich interoceptive conditioning history with the stimulus effects of nicotine. Our long-term objective is to understand how this conditioning history alters the trajectory of use and misuse in individuals and, in doing so, provide new clues on how to improve cessation programs. To this end, we recently developed an innovative new approach using rats that merges interoceptive conditioning of intravenous (IV) nicotine with its later self-administration. When IV nicotine is repeatedly paired with an appetitive reinforcer (i.e., sucrose), this conditioning history dose- and sex- dependently increases nicotine self-administration (21 to 126%)—an effect more profound in female rats. Leveraging the methodological strengths of this new approach, we address three Aims in the present proposal. Aim 1 will assess whether the need to recall the learning after a retention interval alters the strength of the conditioned reinforcing effects of nicotine. Aim 2 will determine whether the addition of a weak reinforcer during self-administration interacts with nicotine and its newly acquired conditioned reinforcing effects. Aim 3 will examine whether an external (exteroceptive) stimulus will compete with the interoceptive nicotine stimulus for conditioned reinforcing value, thus weakening its later impact on nicotine intake. A fundamental understanding of such factors that influence the effect of interoceptive conditioning with nicotine will refine and advance our theoretical models. These advancements will provide foundational research for other basic scientists and clues for clinical scientists and healthcare providers working to improve approaches to treating nicotine use disorder.