Pharmacological interventions to diminish nicotine associated responding

说明(申请人提供)：长期使用烟草与心脏病和多种癌症的显著增加有关；即使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。关于药物调节的研究和理论大多将尼古丁视为一种无条件的刺激或增强剂，与其他刺激(香烟、情景线索)联系在一起，这些刺激与尼古丁的生理效应可靠地共存。对尼古丁依赖的发展和坚持性也很重要的一个未被研究的领域是尼古丁的药理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)的内感刺激的能力。事实上，最近研究人员和从业者对内感条件作用的认识有所提高，这对一系列精神病理和疾病--包括成瘾--的作用。我们已经开发了一个临床前模型来研究尼古丁的相互感觉条件作用。有吸食尼古丁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，也就是说，预期的觅食。迄今为止最具挑衅性的发现是，尼古丁刺激的条件反射可以通过反复非强化的呈现替代药物(即消退)来减弱，这种替代药物与尼古丁具有共同的感觉刺激效应。 在varenicline(戒烟助剂Chantix(®))、安非他酮(戒烟助剂Zyban®)和去甲尼古丁(一种潜在的戒烟助剂，是烟草中尼古丁和少量生物碱的代谢物)中已经看到了这种“消退转移”。这项拟议的研究将以这一令人兴奋的发现为基础，通过更仔细地检查深化灭绝转移的新方法，从而减少尼古丁对后天食欲行为的控制，从而建立在程序上。通过这样做，本应用中的实验为该领域引入了研究相互感觉刺激的新方法，开始填补科学文献中的一个重大空白，促进我们对涉及尼古丁的消退过程的理解，并阐明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.