Why flavored vape products may be attractive: Green apple tobacco flavor elicits reward-related behavior, upregulates nAChRs on VTA dopamine neurons, and alters midbrain dopamine and GABA neuron function
Why flavored vape products may be attractive: Green apple tobacco flavor elicits reward-related behavior, upregulates nAChRs on VTA dopamine neurons, and alters midbrain dopamine and GABA neuron function
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DOI：
10.1016/j.neuropharm.2019.107729
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发表时间：
2019-11-01
影响因子：
4.7
通讯作者：
Henderson, Brandon J.
中科院分区：
文献类型：
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作者：
Avelar, Alicia J.;Akers, Austin T.;Henderson, Brandon J.
虽然尼古丁是烟草产品中的主要成瘾成分，但随着电子尼古丁输送系统 (ENDS) 的日益普及，附加口味也成为人们关注的问题。为此，我们开始研究流行的烟草和 ENDS 口味。在这里，我们检查了金合欢醇（一种用于 ENDS 电子烟液中青苹果和水果香料的化学香料），看其产生奖励相关行为的能力。使用雄性和雌性 3-6 个月大的 C57BL/6 J 小鼠以及 0.1、1 和 10 mg/kg 的金合欢醇剂量，我们在条件性位置偏好测定中发现了性别依赖性效应：单独的金合欢醇仅在雄性小鼠中产生奖励相关行为。尽管存在这种性别依赖性效应，1.0 mg/kg 金合欢醇仍能增强雄性和雌性小鼠的运动活性。为了了解法尼醇对奖励相关行为的影响，我们使用全细胞膜片钳电生理学和共聚焦显微镜来研究假定的多巴胺和 GABA 神经元的变化。对于这些方法，我们利用含有荧光烟碱乙酰胆碱受体（nAChR）的转基因小鼠。我们对雄性小鼠进行的电生理学测定表明，金合欢醇治疗增加了腹侧被盖区 (VTA) 多巴胺神经元的放电频率，这可能是由于 GABA 神经元的抑制音降低所致。我们的显微镜检测显示，金合欢醇治疗会显着上调雄性小鼠的 α 6* nAChR，但不会显着上调雌性小鼠。在额外的电生理学测定中观察到的 α 6* nAChR 功能增加支持了这一点。这些数据提供的证据表明，流行的烟草香料可能会改变与吸烟相关的行为，并促使人们需要检查其他 ENDS 香料。
While nicotine is the primary addictive component in tobacco products, additional flavors have become a concern with the growing popularity of electronic nicotine delivery systems (ENDS). For this reason, we have begun to investigate popular tobacco and ENDS flavors. Here, we examined farnesol, a chemical flavorant used in green apple and fruit flavors in ENDS e-liquids, for its ability to produce reward-related behavior. Using male and female 3-6 month old C57BL/6 J mice and farnesol doses of 0.1, 1, and 10 mg/kg we identified a sex-dependent effect in a conditioned place preference assay: farnesol-alone produces reward-related behavior in only male mice. Despite this sex-dependent effect, 1.0 mg/kg farnesol enhances locomotor activity in both male and female mice. To understand famesol's effect on reward-related behavior, we used whole-cell patch-clamp electrophysiology and confocal microscopy to investigate changes in putative dopamine and GABA neurons. For these approaches, we utilized genetically modified mice that contain fluorescent nicotinic acetylcholine receptors (nAChRs). Our electrophysiological assays with male mice revealed that farnesol treatment increases ventral tegmental area (VTA) dopamine neuron firing frequency and this may be due to a decrease in inhibitory tone from GABA neurons. Our microscopy assays revealed that farnesol treatment produces a significant upregulation of alpha 6* nAChRs in male mice but not female mice. This was supported by an observed increase in alpha 6* nAChR function in additional electrophysiology assays. These data provide evidence that popular tobacco flavorants may alter smoking-related behavior and promote the need to examine additional ENDS flavors.