Department of Medicine, Minneapolis Medical Research Foundation, Minneapolis, MN, USA; Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
Department of Medicine, Minneapolis Medical Research Foundation, Minneapolis, MN, USA.
Drug Alcohol Depend. 2018 Apr 1;185:1-9. doi: 10.1016/j.drugalcdep.2017.11.032. Epub 2018 Feb 1.
Animal models are needed to inform FDA regulation of electronic cigarettes (ECs) because they avoid limitations associated with human studies. We previously reported that an EC refill liquid produced less aversive/anhedonic effects at a high nicotine dose than nicotine alone as measured by elevations in intracranial self-stimulation (ICSS) thresholds, which may reflect the presence of behaviorally active non-nicotine constituents (e.g., propylene glycol) in the EC liquids. The primary objective of this study was to assess the generality of our prior ICSS findings to two additional EC liquids. We also compared effects of "nicotine-free" varieties of these EC liquids on ICSS, as well as binding affinity and/or functional activity of nicotine alone, nicotine-containing EC liquids, and "nicotine-free" EC liquids at nicotinic acetylcholine receptors (nAChRs).
Nicotine alone and nicotine dose-equivalent concentrations of both nicotine-containing EC liquids produced similar lowering of ICSS thresholds at low to moderate nicotine doses, indicating similar reinforcement-enhancing effects. At high nicotine doses, nicotine alone elevated ICSS thresholds (a measure of anhedonia-like behavior) while the EC liquids did not. Nicotine-containing EC liquids did not differ from nicotine alone in terms of binding affinity or functional activity at nAChRs. "Nicotine-free" EC liquids did not affect ICSS, but bound with low affinity at some (e.g., α4ß2) nAChRs.
These findings suggest that non-nicotine constituents in these EC liquids do not contribute to their reinforcement-enhancing effects. However, they may attenuate nicotine's acute aversive/anhedonic and/or toxic effects, which may moderate the abuse liability and/or toxicity of ECs.
动物模型对于告知 FDA 对电子烟的监管是必要的，因为它们避免了与人体研究相关的限制。我们之前报告过，电子烟液补充剂在高尼古丁剂量下产生的厌恶/快感缺失效应比尼古丁单独使用时要少，这可以通过颅内自我刺激 (ICSS) 阈值的升高来衡量，这可能反映了电子烟液中存在行为活跃的非尼古丁成分（例如，丙二醇）。本研究的主要目的是评估我们之前的 ICSS 研究结果在另外两种电子烟液中的普遍性。我们还比较了这些电子烟液的“无尼古丁”品种对 ICSS 的影响，以及尼古丁单独、含尼古丁的电子烟液和“无尼古丁”电子烟液在烟碱型乙酰胆碱受体 (nAChR) 上的结合亲和力和/或功能活性。
尼古丁单独和两种含尼古丁的电子烟液的尼古丁等效浓度在低至中等尼古丁剂量下都能产生类似的 ICSS 阈值降低，表明具有相似的增强强化作用。在高尼古丁剂量下，尼古丁单独提高了 ICSS 阈值（一种快感缺失样行为的衡量标准），而电子烟液则没有。在 nAChR 方面，含尼古丁的电子烟液与尼古丁单独使用在结合亲和力或功能活性方面没有差异。“无尼古丁”电子烟液不会影响 ICSS，但在某些 nAChR（例如，α4β2）上具有低亲和力的结合。
这些发现表明，这些电子烟液中的非尼古丁成分不会导致其增强强化作用。然而，它们可能会减轻尼古丁的急性厌恶/快感缺失和/或毒性作用，这可能会减轻电子烟的滥用倾向和/或毒性。
