Smethells J R, S Wilde, P Muelken, Mg LeSage, Ap Harris
Hennepin Healthcare Research Institute, Minneapolis, MN, USA.
Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
bioRxiv. 2024 Jul 16:2024.07.12.603310. doi: 10.1101/2024.07.12.603310.
β-Nicotyrine (β-Nic) is a unique minor alkaloid constituent in electronic nicotine delivery systems (ENDS) that is derived from nicotine (Nic) degradation and can reach 25% of Nic concentrations in ENDS aerosol. β-Nic slows Nic metabolism and prolongs systemic Nic exposure, which may alter the discriminability of Nic. The present study sought to examine β-Nic has interoceptive effects itself, and if it alters the subjective effects ENDS products within a drug-discrimination paradigm.
The pharmacodynamics of β-Nic were examined in vitro, and a nicotine discrimination paradigm was used to determine if β-Nic (0 - 5.0 mg/kg) shares discriminative stimulus properties with Nic (0.2 mg/kg) in male (n = 13) and female (n = 14) rats after 10- & 60-min β-Nic pretreatment delays. A second group of rats was trained to discriminate β-Nic and Nornicotine (Nornic) from saline to determine if β-Nic alone has interoceptive properties and whether they are similar to Nornic.
β-Nic had similar binding affinity and efficacy at the α4β2 nicotinic receptor subtype as Nornic, ~50% of Nic efficacy. However, β-Nic only weakly substituted for Nic during substitution testing in female rats, but not males, whereas Nornic fully substituted for Nic. Combination testing at the 10 and 60-min pretreatment intervals showed that β-Nic dose-dependently increased the duration of nicotine's discriminative stimulus effects, especially at the 60-min delay. Drug naïve rats could reliably discriminate Nornic, but not β-Nic, from Sal.
β-Nic increased and prolonged the interoceptive stimulus properties of Nic, suggesting it may alter to the abuse liability of ENDS through its ability to slow Nic metabolism.
β-烟碱（β-Nic）是电子尼古丁传送系统（ENDS）中一种独特的微量生物碱成分，它由尼古丁（Nic）降解产生，在ENDS气溶胶中的浓度可达Nic浓度的25%。β-Nic减缓Nic代谢并延长全身Nic暴露时间，这可能会改变Nic的辨别能力。本研究旨在检验β-Nic本身是否具有内感受效应，以及它在药物辨别范式中是否会改变ENDS产品的主观效应。
在体外检测β-Nic的药效学，采用尼古丁辨别范式来确定在雄性（n = 13）和雌性（n = 14）大鼠中，经过10分钟和60分钟的β-Nic预处理延迟后，β-Nic（0 - 5.0毫克/千克）是否与Nic（0.2毫克/千克）具有相同的辨别刺激特性。第二组大鼠被训练从盐水中辨别β-Nic和去甲烟碱（Nornic），以确定单独的β-Nic是否具有内感受特性，以及它们是否与Nornic相似。
β-Nic在α4β2烟碱受体亚型上具有与Nornic相似的结合亲和力和效能，约为Nic效能的50%。然而，在替代试验中，β-Nic在雌性大鼠中仅微弱地替代了Nic，在雄性大鼠中则不然，而Nornic完全替代了Nic。在10分钟和60分钟预处理间隔的联合试验表明，β-Nic剂量依赖性地增加了尼古丁辨别刺激效应的持续时间，尤其是在60分钟延迟时。未接触过药物的大鼠能够可靠地从盐水中辨别出Nornic，但不能辨别出β-Nic。
β-Nic增强并延长了Nic的内感受刺激特性，表明它可能通过减缓Nic代谢的能力改变ENDS的滥用可能性。
