Caine S Barak, Collins Gregory T, Thomsen Morgane, Wright Curtis, Lanier Ryan K, Mello Nancy K
Alcohol & Drug Abuse Research Center.
Rock Creek Pharmaceuticals.
Exp Clin Psychopharmacol. 2014 Feb;22(1):9-22. doi: 10.1037/a0035749.
Tobacco use is associated with lethal diseases in an estimated 440,000 persons in the United States each year (Centers for Disease Control and Prevention, 2005). Successful smoking quit-rates are estimated at 5%-8%, even though a quarter of those attempts included use of smoking-cessation aids (Messer et al., 2008; Henningfield et al., 2009). Current projections are that 16% of the U.S. population-35 million people-will still smoke in 2025, thus more effective smoking-cessation aids are urgently needed (Pollock et al., 2009). The minor tobacco alkaloids may be promising candidates, but further research is necessary (Hoffman & Evans, 2013). Accordingly, we systematically evaluated the minor tobacco alkaloids nornicotine, anabasine, and anatabine using assays of behavioral tolerability, nicotine withdrawal, nicotine discrimination, and nicotine self-administration in male rodents. At doses that were well tolerated, all 3 minor alkaloids dose-dependently engendered robust substitution for a nicotine discriminative stimulus in mice (0.32 mg/kg, IP), and anabasine attenuated nicotine withdrawal. When the ED50 dose of each alkaloid was administered in combination with nicotine, the discriminative stimulus effects of nicotine were not enhanced by any of the alkaloids, and anatabine blunted nicotine's effects. In drug self-administration studies, only nornicotine was self-administered by rats that self-administered nicotine intravenously; anabasine and anatabine had no reinforcing effects. Moreover, prior administration of each of the minor tobacco alkaloids dose-dependently decreased nicotine self-administration. Collectively these results suggest that the minor tobacco alkaloids may substitute for the subjective effects of nicotine and attenuate withdrawal and craving without the abuse liability of nicotine.
在美国，每年估计有44万人因吸烟患上致命疾病（疾病控制与预防中心，2005年）。尽管四分之一的戒烟尝试使用了戒烟辅助工具，但成功戒烟率估计仅为5%-8%（梅塞尔等人，2008年；亨宁菲尔德等人，2009年）。目前的预测表明，到2025年，美国仍将有16%的人口（3500万人）吸烟，因此迫切需要更有效的戒烟辅助工具（波洛克等人，2009年）。烟草中的次要生物碱可能是有前景的候选药物，但还需要进一步研究（霍夫曼和埃文斯，2013年）。因此，我们使用行为耐受性、尼古丁戒断、尼古丁辨别和尼古丁自我给药试验，对雄性啮齿动物体内的次要烟草生物碱降烟碱、新烟草碱和假木贼碱进行了系统评估。在耐受性良好的剂量下，所有3种次要生物碱均能剂量依赖性地在小鼠（腹腔注射0.32mg/kg）中有力地替代尼古丁辨别刺激，且新烟草碱可减轻尼古丁戒断症状。当将每种生物碱的半数有效剂量（ED50）与尼古丁联合给药时，任何一种生物碱均未增强尼古丁的辨别刺激作用，且假木贼碱减弱了尼古丁的作用。在药物自我给药研究中，只有降烟碱能被静脉注射尼古丁的大鼠自我给药；新烟草碱和假木贼碱没有强化作用。此外，预先给予每种次要烟草生物碱均能剂量依赖性地减少尼古丁自我给药。总体而言，这些结果表明，次要烟草生物碱可能替代尼古丁的主观效应，减轻戒断症状和渴望，且无尼古丁的滥用可能性。
