Pharmacological interventions to diminish nicotine associated responding

描述（由申请人提供）：长期吸烟与心脏病和多种癌症的显著增加有关;即使是非烟草使用者的健康也受到二手烟的负面影响。更好地了解导致尼古丁依赖的因素对个人和社会的潜在好处是巨大的。条件反射是促成成瘾循环的一个重要因素。关于药物条件反射的研究和理论通常将尼古丁视为一种无条件刺激或刺激物，与其他刺激（香烟，情境线索）相关联，这些刺激与其生理效应可靠地共同发生。对尼古丁依赖的发展和持续性也很重要的一个未充分研究的领域是尼古丁的药理作用作为其他强化事件（同伴接受、酒精、工作休息、缓解压力等）的内感受性刺激的能力。事实上，最近研究者和实践者越来越意识到内感受性条件反射在包括成瘾在内的各种精神病理学和疾病中的作用。我们已经开发了一个临床前模型来研究尼古丁的内感受性条件反射。具有尼古丁食欲学习史的大鼠将显示出受尼古丁刺激控制的条件反射的证据;即预期的食物寻找。迄今为止最具挑衅性的发现是，对尼古丁刺激的条件反射可以通过替代药物的重复非强化呈现而减弱（即，消光），与尼古丁共享内感受性刺激效应。 在伐尼克兰（戒烟辅助剂Chantix ®）、安非他酮（戒烟辅助剂Zyban®）和去甲尼古丁（一种潜在的戒烟辅助剂，是烟草中尼古丁和次要生物碱的代谢物）中观察到了这种“消退转移”。这项拟议中的研究将以这一令人兴奋的发现为基础，通过更密切地研究加深灭绝转移的新方法，从而减少尼古丁对后天食欲行为的控制。在这样做的过程中，本申请中的实验引入了用于研究内感受性刺激的新方法，开始填补了科学文献中的重大空白，推进了我们对涉及尼古丁的消退过程的理解，并阐明了尼古丁刺激和治疗相关配体的性质。

DESCRIPTION (provided by applicant): 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. The potential benefits to the individual and society that would come from a better understanding of the factors that contribute to nicotine dependence are enormous. Conditioning is one important factor that contributes to the addiction cycle. Research and theory on drug conditioning most often treats nicotine as an unconditioned stimulus or reinforcer that enters into an association with other stimuli (cigarette, situational cues) that reliably co-occur with its physiological effects. An understudied area that is also important for the development and tenacity of nicotine dependence is the ability of the pharmacological effects of nicotine to serve as an interoceptive stimulus for other reinforcing events (peer acceptance, alcohol, work breaks, stress relief, etc.). Indeed, there has been a recent rise in investigators' and practitioners' awareness of the role of interoceptive conditionin to a wide range of psychopathologies and diseases-including addiction. We have developed a preclinical model to study interoceptive conditioning with nicotine. Rats that have an appetitive learning history with nicotine will show evidence of conditioning controlled by the nicotine stimulus; that is, anticipatory food-seeking. The most provocative finding to date is that conditioning to the nicotine stimulus can be weakened by repeated non- reinforced presentation of an alternative drug (i.e., extinction) that shares interoceptive stimulus effects with nicotine. This "transfer of extinction" has been seen with varenicline (the smoking cessation aid Chantix(®), bupropion (the smoking cessation aid Zyban®), and nornicotine (a potential smoking cessation aid that is a metabolite of nicotine and minor alkaloid in tobacco). The proposed research will build programmatically on this exciting finding by more closely examining novel approaches to deepening transfer of extinction, hence diminishing the control of nicotine over acquired appetitive behavior. In doing so, the experiments in this application introduce new methods for studying interoceptive stimuli to the field, begin to fill a significant gap in the scientific literature, advance our understanding of extinction processes involving nicotine, and elucidate the nature of the nicotine stimulus and treatment-relevant ligands.