The Novel CYP2A6 Inhibitor, DLCI-1, Decreases Nicotine Self-Administration in Mice. Other Scholarly Work

Chen, Yen-Chu, Fowler, James P, Wang, Jing et al. (2020). The Novel CYP2A6 Inhibitor, DLCI-1, Decreases Nicotine Self-Administration in Mice. . 372(1), 21-29. 10.1124/jpet.119.260653

cited authors

  • Chen, Yen-Chu; Fowler, James P; Wang, Jing; Watson, Christy JW; Sherafat, Yasmine; Staben, Andres; Lazarus, Philip; Denton, Travis T; Fowler, Christie D

fiu authors

abstract

  • 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 STATEMENT: Current 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.

publication date

  • January 1, 2020

keywords

  • Animals
  • Cytochrome P-450 CYP2A6
  • Enzyme Inhibitors
  • Female
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nicotine
  • Smoking Cessation Agents
  • Thiophenes
  • Tobacco Use Disorder

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • 21

end page

  • 29

volume

  • 372

issue

  • 1