The Novel CYP2A6 Inhibitor, DLCI-1, Decreases Nicotine Self-Administration in Mice
The Novel CYP2A6 Inhibitor, DLCI-1, Decreases Nicotine Self-Administration in Mice
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DOI：
10.1124/jpet.119.260653
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发表时间：
2020-01-01
影响因子：
3.5
通讯作者：
Fowler, Christie D.
中科院分区：
文献类型：
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作者：
Chen, Yen-Chu;Fowler, James P.;Fowler, Christie D.
在使用烟草和电子烟期间，尼古丁主要在人体肝脏中通过细胞色素 P450 2A6 (CYP2A6) 代谢。鉴于较慢的 CYP2A6 代谢与较不易产生尼古丁依赖有关，当前的研究试图验证一种新型 CYP2A6 抑制剂（5-(4-乙基吡啶-3-基)噻吩-2-基)甲胺 (DLCI-1) 对静脉内尼古丁自我给药的影响。雄性和雌性小鼠被训练在日常训练中自我施用尼古丁。一旦达到稳定的反应，在尼古丁治疗之前进行 DLCI-1 或媒介物控制。我们发现，较低 25 毫克/千克和中等 50 毫克/千克剂量的 DLCI-1 会导致男性和女性尼古丁摄入量显着减少。进一步显示，DLCI-1 在减少尼古丁摄入量方面比 1 mg/kg 中等剂量的安非他酮更有效，并且没有产生 75 mg/kg 高剂量安非他酮所发现的不良行为影响。尽管用 DLCI-1 治疗的小鼠自身施用的尼古丁显着减少，但观察到类似的尼古丁介导的运动行为影响。结合自我给药过程中尼古丁代谢物的分析，这些发现支持了这样的论点：阻断肝脏尼古丁代谢将允许在较低尼古丁剂量下类似地激活烟碱乙酰胆碱受体。此外，DLCI-1 的这些作用是尼古丁自我给药所特有的，因为 DLCI-1 在食物自我给药期间不会导致任何行为变化。综上所述，这些研究证实 DLCI-1 是一种减少尼古丁消耗的新型化合物，从而可能促进戒烟和戒烟。 意义声明 目前用于戒烟和戒烟的药理学方法在促进长期戒烟方面只能取得有限的效果。在这项工作中，我们表征了一种新型化合物（5-（4-乙基吡啶-3-基）噻吩-2-基）甲胺（DLCI-1）的作用，它抑制代谢尼古丁的主要酶，并且我们报告雄性和雌性小鼠静脉注射尼古丁的自我给药显着减少，支持DLCI-1作为新型戒烟药物的潜力。
During tobacco and e-cigarette use, nicotine is mainly metabolized in the human liver by cytochrome P450 2A6 (CYP2A6). Given that a slower CYP2A6 metabolism has been associated with less vulnerability to develop nicotine dependence, the current studies sought to validate a novel CYP2A6 inhibitor, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), for its effects on intravenous nicotine self-administration. Male and female mice were trained to self-administer nicotine across daily sessions. Once stable responding was achieved, DLCI-1 or vehicle control was administered prior to nicotine sessions. We found that the lower 25 mg/kg and moderate 50 mg/kg doses of DLCI-1 induced a significant decrease in nicotine intake for both males and females. DLCI-1 was further shown to be more effective than a moderate 1 mg/kg dose of bupropion on reducing nicotine intake and did not exert the adverse behavioral effects found with a high 75 mg/kg dose of bupropion. Although mice treated with DLCI-1 self-administered significantly less nicotine, similar nicotine-mediated behavioral effects on locomotion were observed. Together, along with the analysis of nicotine metabolites during self-administration, these findings support the contention that blocking hepatic nicotine metabolism would allow for similar activation of nicotinic acetylcholine receptors at lower nicotine doses. Moreover, these effects of DLCI-1 were specific to nicotine self-administration, as DLCI-1 did not result in any behavioral changes during food self-administration. Taken together, these studies validate DLCI-1 as a novel compound to decrease nicotine consumption, which may thereby promote tobacco and nicotine product cessation.SIGNIFICANCE STATEMENTCurrent pharmacological approaches for nicotine and tobacco cessation have only been able to achieve limited efficaciousness in promoting long-term abstinence. In this work, we characterize the effects of a novel compound, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), which inhibits the main enzyme that metabolizes nicotine, and we report a significant decrease in intravenous nicotine self-administration in male and female mice, supporting the potential of DLCI-1 as a novel tobacco cessation pharmacotherapeutic.