Interoceptive conditioning with nicotine: Changes in abuse liability

项目摘要 尼古丁是烟草中主要的成瘾成分。对个人而言，长期使用烟草与 心脏病和多种癌症的发病率显著增加；即使是非吸烟者的健康也 受到二手烟的负面影响。这种成瘾有一些重要的性别差异， 对健康的影响。女性平均比男性花更少的时间戒烟，减少 尝试戒烟，戒烟时间更短，复发率更高，从尼古丁中获益更少 替代疗法。显然，个人和社会的巨大收益将来自于一个更好的 了解导致尼古丁依赖的因素。与药物有关的环境刺激 例如尼古丁可能是寻求毒品行为的强大调节器。另一个重要因素是 尼古丁依赖的发展和坚韧是尼古丁作为一种药物的药理作用 感觉间(内部)刺激与其他增强剂形成条件性联系/非条件性 刺激[USS(同伴接纳、饮酒、工作休息、缓解压力)]。因此，随着时间的推移，吸烟者有一种 在尼古丁的刺激作用下，有机会发展丰富的食欲调理历史。这是获得的 强化价值可能有助于尼古丁成瘾的坚韧。使用一种新开发的 临床前动物模型创新性地融合了内感调节和尼古丁自我给药， 本申请将严格检验这一假设，即在胃口内感受器之后 尼古丁的条件化历史，尼古丁刺激将获得条件性强化价值， 加剧尼古丁摄取行为的持久性。为此，具体目标将审查如何 药物摄取的增加与尼古丁刺激的显著程度(剂量)不同(目标1)，评估协同作用 尼古丁和乙醇之间通过使用乙醇或蔗糖-乙醇溶液作为US(目标2)，并实施 一种创新的消光方案，旨在削弱获得性尼古丁的条件性强化价值，以 在雌性和雄性大鼠中，更大程度上不仅仅是简单地不强化目标刺激(目标3)。

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; even the health of non-tobacco users is negatively affected by second-hand smoke. There are some important sex differences in this addiction and its health consequences. Women on average take less time than men to become nicotine dependent, make fewer attempts to quit smoking, abstain for less time, relapse at higher rates, and benefit less from nicotine replacement therapy. Clearly, enormous gains to the individual and society would come from a better understanding of factors that contribute to nicotine dependence. Environmental stimuli associated with drugs such as nicotine can be powerful modulators of drug-seeking behavior. Another important factor to the development and tenacity of nicotine dependence is the pharmacological effects of nicotine serving as an interoceptive (internal) stimulus entering into a conditioned association with other reinforcers/unconditioned stimuli [USs (peer acceptance, alcohol, work breaks, stress relief)]. Consequently, over time, a smoker has an opportunity to develop a rich appetitive conditioning history with the stimulus effects of nicotine. This acquired reinforcing value likely contributes to the tenacity of the nicotine addiction. Using a newly developed preclinical animal model that innovatively merges interoceptive conditioning with nicotine self-administration, the present application will rigorously test the hypothesis that following an appetitive interoceptive conditioning history with nicotine, the nicotine stimulus will acquire conditioned reinforcing value that exacerbates the persistence of nicotine-taking behavior. To this end, the Specific Aims will examine how such enhancement of drug intake varies with the salience (dose) of the nicotine stimulus (Aim 1), assess the synergy between nicotine and ethanol by using ethanol or sucrose-ethanol solution as the US (Aim 2), and implement an innovative extinction protocol designed to weaken the acquired conditioned reinforcing value of nicotine to a greater extent than just simple non-reinforcement of the target stimulus (Aim 3) in female and male rats.