Pharmacological interventions to diminish nicotine associated responding

描述（由申请人提供）：长期烟草使用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。条件反射是导致成瘾循环的一个重要因素。药物条件作用的研究和理论通常将尼古丁视为一种无条件刺激或强化物，它与其他刺激（香烟、情境线索）相关联，这些刺激与尼古丁的生理作用可靠地共同发生。一个未被充分研究的领域对尼古丁依赖的发展和持久性也很重要，那就是尼古丁的药理学效应作为其他强化事件（同伴接受、酒精、工作休息、压力缓解等）的内感受刺激的能力。事实上，最近研究者和实践者对内感受性条件作用在广泛的精神病理学和疾病（包括成瘾）中的作用的认识有所提高。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。对尼古丁有食欲学习史的大鼠将显示出尼古丁刺激控制的条件反射的证据；也就是说，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反复非强化的替代药物（即消失）来减弱，这种替代药物与尼古丁具有相同的内感受性刺激作用。

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.