Behavioral Neuroscience Program, Department of Psychology, University at Buffalo, Buffalo, New York.
Department of Psychology, University of Nebraska-Lincoln.
Behav Pharmacol. 2023 Feb 1;34(1):12-19. doi: 10.1097/FBP.0000000000000707. Epub 2022 Nov 3.
Varenicline (Chantix) is an FDA-approved smoking cessation aid that is pharmacologically similar to nicotine, the primary addictive component found within tobacco. In support of this similarity, previous drug discrimination research in rats has reported that the internal or interoceptive stimulus effects of nicotine and varenicline share stimulus elements. Those shared elements appear to be mediated, in part, by overlapping action at alpha4beta2-containing nicotinic acetylcholine receptors (nAChRs). The research supporting this conclusion, however, has only used nicotine, and not varenicline, as the training drug. Accordingly, we used the discriminated goal tracking (DGT) task in which 1 mg/kg varenicline signaled intermittent access to sucrose. On separate intermixed saline days, sucrose was not available. Rats acquired the discrimination as measured by a differential increase in dipper entries (goal tracking) evoked by varenicline. These rats then received a series of tests with several doses of varenicline, nicotine, nornicotine (a metabolite of nicotine and tobacco alkaloid), sazetidine-A (a partial alpha4beta2 agonist), PHA-543613 (an alpha7 agonist), and bupropion (a norepinephrine and dopamine reuptake inhibitor). Control of goal tracking by varenicline was dose-dependent. Nicotine and nornicotine evoked responding comparable to the varenicline training dose indicating full substitution. Sazetidine-A partially substituted for the varenicline stimulus, whereas bupropion and PHA-543613 evoked little to no varenicline-like responding. These findings indicate that varenicline can serve as the training stimulus in the DGT task. Further, stimulus control of varenicline in the DGT task is driven by its partial agonist activity at alpha4beta2-containing nAChRs. The use of this approach could lead to a better understanding of the pharmacological action of varenicline and help guide treatment geared towards tobacco cessation through a more targeted development of novel synthetically designed, subunit-specific pharmacological interventions.
伐伦克林（Chantix）是一种获得美国食品药品监督管理局批准的戒烟辅助药物，其药理学作用类似于尼古丁，尼古丁是烟草中主要的成瘾成分。支持这种相似性，先前在大鼠中的药物辨别研究报告称，尼古丁和伐伦克林的内部或内感受性刺激效应共享刺激元素。这些共享的元素似乎部分是由重叠作用于包含α4β2 的烟碱型乙酰胆碱受体（nAChRs）介导的。然而，支持这一结论的研究仅使用尼古丁而不是伐伦克林作为训练药物。因此，我们使用了区分目标跟踪（DGT）任务，其中 1mg/kg 伐伦克林表示间歇性获得蔗糖。在单独的混合盐水日中，蔗糖不可用。大鼠通过伐伦克林诱发的差异增加（目标跟踪）获得了辨别能力。然后，这些大鼠接受了一系列使用几种剂量的伐伦克林、尼古丁、去甲烟碱（尼古丁和烟草生物碱的代谢物）、萨泽替丁-A（部分α4β2 激动剂）、PHA-543613（α7 激动剂）和安非他酮（去甲肾上腺素和多巴胺再摄取抑制剂）的测试。伐伦克林对目标跟踪的控制是剂量依赖性的。尼古丁和去甲烟碱诱发的反应与伐伦克林的训练剂量相当，表明完全替代。萨泽替丁-A 部分替代了伐伦克林的刺激，而安非他酮和 PHA-543613 则引起很少或没有类似伐伦克林的反应。这些发现表明，伐伦克林可以作为 DGT 任务中的训练刺激。此外，DGT 任务中伐伦克林的刺激控制是由其在包含α4β2 的 nAChRs 上的部分激动剂活性驱动的。这种方法的使用可以帮助我们更好地理解伐伦克林的药理学作用，并通过更有针对性地开发新的合成设计、亚基特异性药理学干预措施，为烟草戒断治疗提供指导。
