Wang Tengfei, Wang Bin, Chen Hao
Department of Pharmacology, University of Tennessee Health Science Center Memphis, TN, USA.
College of Pharmacy, Shaanxi University of Chinese Medicine Xian Yang, Shaanxi, China.
Front Behav Neurosci. 2014 Dec 16;8:437. doi: 10.3389/fnbeh.2014.00437. eCollection 2014.
Menthol is preferred by ~25% of smokers and is the most common flavoring additive in tobacco and electronic cigarettes. Although some clinical studies have suggested that menthol facilitates the initiation of smoking and enhances the dependence on nicotine, many controversies remain. Using licking as the operant behavior, we found that adolescent rats self-administering nicotine (30μg/kg/infusion, free base, i.v.) with contingent oral menthol (60μl, 0.01% w/v) obtained significantly more infusions than rats receiving a vehicle cue or rats self-administering i.v. saline with a menthol cue. Rats yoked to their menthol-nicotine masters emitted significantly fewer licks on the active spouts, indicating that contingent pairing between nicotine and menthol is required for sustained nicotine intake. Rats that self-administered nicotine with a menthol cue also exhibited a long-lasting extinction burst and robust reinstatement behavior, neither of which were observed in rats that self-administered saline with a menthol cue. The cooling sensation of menthol is induced by activating the transient receptor potential M8 (TRPM8) channel. When WS-23, an odorless agonist of the TRPM8 channel, was used as a contingent cue for nicotine, the rats obtained a similar number of nicotine infusions as the rats that were provided a menthol cue and exhibited a strong preference for the active spout. In contrast, highly appetitive taste and odor cues failed to support nicotine self-administration. These data indicated that menthol, likely by inducing a cooling sensation, becomes a potent conditioned reinforcer when it is contingently delivered with nicotine. Together, these results provide a key behavioral mechanism by which menthol promotes the use of tobacco products or electronic cigarettes.
约25%的吸烟者更喜欢薄荷醇，它是烟草和电子烟中最常见的调味添加剂。尽管一些临床研究表明薄荷醇有助于开始吸烟并增强对尼古丁的依赖，但仍存在许多争议。以舔舐作为操作性行为，我们发现，青春期大鼠静脉注射尼古丁（30μg/kg/次，游离碱）并伴有口腔给予薄荷醇（60μl，0.01% w/v）时，其获得的注射次数显著多于接受溶剂提示的大鼠或静脉注射生理盐水并伴有薄荷醇提示的大鼠。与接受薄荷醇-尼古丁配对的大鼠相连的大鼠在活动喷口上的舔舐次数显著减少，这表明尼古丁和薄荷醇之间的偶然配对是持续摄入尼古丁所必需的。接受薄荷醇提示自我注射尼古丁的大鼠还表现出持久的消退爆发和强烈的复吸行为，而接受薄荷醇提示自我注射生理盐水的大鼠均未观察到这些行为。薄荷醇的清凉感是通过激活瞬时受体电位M8（TRPM8）通道诱导产生的。当TRPM8通道的无味激动剂WS-23用作尼古丁的偶然提示时，大鼠获得的尼古丁注射次数与接受薄荷醇提示的大鼠相似，并对活动喷口表现出强烈偏好。相比之下，极具吸引力的味觉和气味提示无法支持尼古丁的自我给药。这些数据表明，薄荷醇可能通过诱导清凉感，在与尼古丁偶然给药时成为一种有效的条件强化物。总之，这些结果提供了一种关键的行为机制，通过该机制薄荷醇促进了烟草制品或电子烟的使用。
