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.
Pharmacol Biochem Behav. 2017 Oct;161:1-5. doi: 10.1016/j.pbb.2017.08.011. Epub 2017 Sep 1.
The FDA recently extended their regulatory authority to electronic cigarettes (ECs). Because the abuse liability of ECs is a leading concern of the FDA, animal models are urgently needed to identify factors that influence the relative abuse liability of these products. The ability of tobacco products to induce nicotine dependence, defined by the emergence of anhedonia and other symptoms of nicotine withdrawal following cessation of their use, contributes to tobacco abuse liability. The present study compared the severity of precipitated withdrawal during chronic infusion of nicotine alone or nicotine-dose equivalent concentrations of three different EC refill liquids in rats, as indicated by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Because these EC liquids contain constituents that may enhance their abuse liability (e.g., minor alkaloids), we hypothesized that they would be associated with greater withdrawal effects than nicotine alone. Results indicated that the nicotinic acetylcholine receptor antagonist mecamylamine precipitated elevations in ICSS thresholds in rats receiving a chronic infusion of nicotine alone or EC liquids (3.2mg/kg/day, via osmotic pump). Magnitude of this effect did not differ between formulations. Our findings indicate that nicotine alone is the primary CNS determinant of the ability of ECs to engender dependence. Combined with our previous findings that nicotine alone and these EC liquids do not differ in other preclinical addiction models, these data suggest that product standards set by the FDA to reduce EC abuse liability should primarily target nicotine, other constituents with peripheral sensory effects (e.g. flavorants), and factors that influence product appeal (e.g., marketing).
美国食品药品监督管理局（FDA）最近扩大了对电子烟（ECs）的监管权限。由于 ECs 的滥用倾向是 FDA 的主要关注点，因此迫切需要动物模型来确定影响这些产品相对滥用倾向的因素。烟草产品引起尼古丁依赖的能力，定义为停止使用后出现快感缺失和其他尼古丁戒断症状，这导致了烟草的滥用倾向。本研究比较了在大鼠中单独输注尼古丁或三种不同 EC 补充液的尼古丁等效浓度慢性输注期间诱发戒断的严重程度，以颅内自我刺激（ICSS）阈值升高为指标（快感缺失样行为）。由于这些 EC 液体含有可能增强其滥用倾向的成分（例如，少量生物碱），我们假设它们与尼古丁单独使用相比会引起更大的戒断效应。结果表明，烟碱型乙酰胆碱受体拮抗剂美加明在接受单独输注尼古丁或 EC 液体（通过渗透压泵以 3.2mg/kg/天的速度）的大鼠中引发了 ICSS 阈值的升高。这种作用的幅度在不同配方之间没有差异。我们的研究结果表明，尼古丁是 EC 产生依赖性的主要中枢决定因素。结合我们之前的研究结果，即尼古丁单独使用和这些 EC 液体在其他临床前成瘾模型中没有差异，这些数据表明，FDA 制定的降低 EC 滥用倾向的产品标准应主要针对尼古丁、具有外周感觉作用的其他成分（例如，调味剂）以及影响产品吸引力的因素（例如，营销）。
