Harris Andrew C, Muelken Peter, Alcheva Aleksandra, Stepanov Irina, LeSage Mark G
Hennepin Healthcare Research Institute, Minneapolis, MN, United States.
Department of Medicine, University of Minnesota, Minneapolis, MN, United States.
Front Neurosci. 2022 May 25;16:868088. doi: 10.3389/fnins.2022.868088. eCollection 2022.
Conventional tobacco cigarettes appear to have greater abuse liability than non-combusted products such as electronic cigarettes (ECs) and nicotine replacement therapy (NRT). This may be due to the higher levels of behaviorally active non-nicotine constituents [e.g., monoamine oxidase (MAO) inhibitors such as β-carbolines] in cigarette smoke (CS) compared to non-combusted products. To evaluate this hypothesis, the current studies compared the relative abuse liability of CS and EC aerosol extracts containing nicotine and a range of non-nicotine constituents to that of nicotine alone (NRT analog) using intracranial self-stimulation (ICSS) in rats. Effects of formulations on brain MAO activity and were also studied to evaluate the potential role of MAO inhibition in the ICSS study. CS extract contained higher levels of several behaviorally active non-nicotine constituents (e.g., the β-carbolines norharmane and harmane) than EC extract. Nicotine alone reduced ICSS thresholds at a moderate nicotine dose, suggesting a reinforcement-enhancing effect that may promote abuse liability, and elevated ICSS thresholds at a high nicotine dose, suggesting an aversive/anhedonic effect that may limit abuse liability. CS extract elevated ICSS thresholds to a greater degree than nicotine alone at high nicotine doses. Effects of EC extract on ICSS did not differ from those of nicotine alone. Finally, CS extract significantly inhibited MAO-A and MAO-B activity , whereas EC extract and nicotine alone did not. None of the formulations inhibited MAO measured . These findings indicate greater acute aversive/anhedonic effects for CS extract compared to nicotine alone, suggesting lower abuse liability. Although confirmation of our findings using other dosing regimens, preclinical addiction models, and tobacco product extracts is needed, these findings suggest that the centrally-mediated effects of MAO inhibitors and other non-nicotine constituents may not account for the greater abuse liability of cigarettes compared to non-combusted products. Nonetheless, identifying the specific constituent(s) mediating the effects of CS extracts in this study could help clarify mechanisms mediating tobacco addiction and inform FDA product standards.
传统烟草香烟似乎比电子烟（ECs）和尼古丁替代疗法（NRT）等非燃烧产品具有更大的滥用可能性。这可能是由于与非燃烧产品相比，香烟烟雾（CS）中具有行为活性的非尼古丁成分[例如，单胺氧化酶（MAO）抑制剂如β-咔啉]水平更高。为了评估这一假设，当前的研究使用大鼠颅内自我刺激（ICSS）比较了含有尼古丁和一系列非尼古丁成分的CS和EC气雾剂提取物与单独尼古丁（NRT类似物）的相对滥用可能性。还研究了制剂对脑MAO活性的影响，以评估MAO抑制在ICSS研究中的潜在作用。CS提取物中几种具有行为活性的非尼古丁成分（例如，β-咔啉去甲哈尔满和哈尔满）的含量高于EC提取物。单独尼古丁在中等尼古丁剂量下降低了ICSS阈值，表明具有增强强化的作用，可能会促进滥用可能性，而在高尼古丁剂量下则提高了ICSS阈值，表明具有厌恶/快感缺失的作用，可能会限制滥用可能性。在高尼古丁剂量下，CS提取物比单独尼古丁更能提高ICSS阈值。EC提取物对ICSS的影响与单独尼古丁没有差异。最后，CS提取物显著抑制MAO-A和MAO-B活性，而EC提取物和单独尼古丁则没有。所有制剂均未抑制所测的MAO。这些发现表明，与单独尼古丁相比，CS提取物具有更大的急性厌恶/快感缺失作用，表明滥用可能性较低。尽管需要使用其他给药方案、临床前成瘾模型和烟草产品提取物来证实我们的发现，但这些发现表明，MAO抑制剂和其他非尼古丁成分的中枢介导作用可能无法解释香烟与非燃烧产品相比更大的滥用可能性。尽管如此，确定本研究中介导CS提取物作用的特定成分可能有助于阐明介导烟草成瘾的机制，并为FDA产品标准提供信息。
