Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 North Torrey Pines Road, SP30-2400, La Jolla, CA 92037, USA.
Psychopharmacology (Berl). 2011 Feb;213(4):715-22. doi: 10.1007/s00213-010-2024-3. Epub 2010 Oct 6.
Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine. Varenicline, a partial α4β2 nicotinic acetylcholine receptor (nAChR) agonist, is effective in reducing nicotine craving and relapse in smokers, suggesting that α4β2 nAChRs may play a key role in nicotine dependence. In rats, the effect of varenicline on nicotine intake has only been studied with limited access to the drug, a model of the positive reinforcing effect of nicotine. Varenicline has not been tested on the increase in motivation to take nicotine in nicotine-dependent rats.
The present study evaluated the effects of varenicline on nicotine intake in rats with extended access to nicotine self-administration (23 h/day), a condition leading to the development of nicotine dependence. We hypothesized that varenicline's effects on nicotine self-administration would be greater in rats with extended than limited access to the drug and after forced abstinence rather than during baseline self-administration.
Varenicline dose-dependently decreased nicotine self-administration in rats with limited (1 h/day) and extended (23 h/day) access. Despite an increased sensitivity to the motivational effects of abstinence on nicotine intake compared with limited-access rats, varenicline was equally effective in decreasing nicotine intake in dependent rats with extended access to nicotine.
These results suggest that α4β2 nAChRs are critical in mediating the positive reinforcing effects of nicotine but may not be a key element underlying the negative reinforcement process responsible for the increased nicotine intake after abstinence in dependent subjects.
大量证据表明，个体主要通过体验尼古丁的精神药理学特性来使用烟草。维拉唑尼是一种部分α4β2 烟碱型乙酰胆碱受体 (nAChR) 激动剂，可有效减少吸烟者对尼古丁的渴望和复吸，这表明α4β2 nAChR 可能在尼古丁依赖中起关键作用。在大鼠中，仅在有限接触药物的情况下（一种尼古丁正强化作用的模型）研究了维拉唑尼对尼古丁摄入的影响。尚未在依赖尼古丁的大鼠中测试维拉唑尼对增加尼古丁摄取动机的影响。
本研究评估了维拉唑尼对延长接触尼古丁（23 小时/天）的大鼠尼古丁摄入的影响，这种条件导致了尼古丁依赖的发展。我们假设维拉唑尼对尼古丁自我给药的影响在接触药物时间延长的大鼠中会比接触药物时间有限的大鼠中更大，并且在强制戒断后而不是在基线自我给药期间。
维拉唑尼剂量依赖性地减少了接触时间有限（1 小时/天）和延长（23 小时/天）的大鼠的尼古丁自我给药。尽管与接触时间有限的大鼠相比，它们对戒断后对尼古丁摄入的动机影响更敏感，但维拉唑尼在接触时间延长的依赖大鼠中同样有效降低尼古丁摄入。
这些结果表明，α4β2 nAChR 在介导尼古丁的正强化作用方面至关重要，但可能不是导致依赖个体戒断后尼古丁摄入增加的负强化过程的关键因素。
