Gazarov Emely A, Zequeira Sabrina, Senetra Alexandria S, Howard John, Sharma Abhisheak, McCurdy Christopher R, Lewis Jada, Bizon Jennifer L, Setlow Barry
Department of Neuroscience, University of Florida, Gainesville, FL, United States.
Department of Psychiatry, University of Florida, Gainesville, FL, United States.
Front Pharmacol. 2023 Aug 28;14:1227220. doi: 10.3389/fphar.2023.1227220. eCollection 2023.
Increased use of cannabis and cannabinoids for recreational and medical purposes has led to a growth in research on their effects in animal models. The majority of this work has employed cannabinoid injections; however, smoking remains the most common route of cannabis consumption. To better model real-world cannabis use, we exposed mice to cannabis smoke to establish the pharmacokinetics of Δ9THC and its metabolites in plasma and brain. To determine the time course of Δ9THC and two major metabolites [11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (11-COOH-THC)], male and female C57BL/6J mice were exposed to smoke from sequentially burning 5 cannabis cigarettes. Following smoke exposure, trunk blood and brains were collected at 6 time points (10-240 min). Plasma and brain homogenates were analyzed for Δ9THC and metabolites using a validated ultraperformance liquid chromatography-tandem mass spectrometry method. To assess effects of age, sex, and mouse strain, we exposed mice of four strains (C57BL/6J, FVB, Swiss Webster, and 129S6/SvEv, aged 4-24 months) to cannabis using the same smoke regimen. Samples were collected 10 and 40 min following exposure. Lastly, to assess effects of dose, C57BL/6J mice were exposed to smoke from burning 3 or 5 cannabis cigarettes, with samples collected 40 min following exposure. The pharmacokinetic study revealed that maximum plasma Δ9THC concentrations (C) were achieved at 10 and 40 min for males and females, respectively, while C for brain Δ9THC was observed at 20 and 40 min for males and females, respectively. There were no age or strain differences in plasma Δ9THC concentrations at 10 or 40 min; however, 129S6/SvEv mice had significantly higher brain Δ9THC concentrations than FVB mice. Additionally, 3 cigarettes produced significantly lower plasma 11-COOH-THC concentrations compared to 5 cigarettes, although dose differences were not evident in plasma or brain concentrations of Δ9THC or 11-OH-THC. Across all experiments, females had higher levels of 11-COOH-THC in plasma compared to males. The results reveal robust sex differences in Δ9THC pharmacokinetics, and lay the groundwork for future studies using mice to model the pharmacodynamics of smoked cannabis.
大麻和大麻素用于娱乐和医疗目的的使用增加，导致了对其在动物模型中作用的研究不断增长。这项工作大部分采用了大麻素注射；然而，吸烟仍然是大麻消费最常见的途径。为了更好地模拟现实世界中的大麻使用情况，我们让小鼠接触大麻烟雾，以确定血浆和大脑中Δ9-四氢大麻酚（Δ9THC）及其代谢物的药代动力学。为了确定Δ9THC和两种主要代谢物[11-羟基-Δ9-四氢大麻酚（11-OH-THC）和11-去甲-9-羧基-Δ9-四氢大麻酚（11-COOH-THC）]的时间进程，将雄性和雌性C57BL/6J小鼠暴露于依次燃烧的5支大麻香烟产生的烟雾中。烟雾暴露后，在6个时间点（10 - 240分钟）采集躯干血和大脑。使用经过验证的超高效液相色谱-串联质谱法分析血浆和脑匀浆中的Δ9THC和代谢物。为了评估年龄、性别和小鼠品系的影响，我们使用相同的烟雾方案让四个品系（4 - 24个月大的C57BL/6J、FVB、瑞士韦伯斯特和129S6/SvEv）的小鼠接触大麻。暴露后10分钟和40分钟采集样本。最后，为了评估剂量的影响，将C57BL/6J小鼠暴露于燃烧3支或5支大麻香烟产生的烟雾中，暴露后40分钟采集样本。药代动力学研究表明，雄性和雌性小鼠血浆中Δ9THC的最大浓度（C）分别在10分钟和40分钟达到，而雄性和雌性小鼠大脑中Δ9THC的C分别在20分钟和40分钟观察到。在10分钟或40分钟时，血浆中Δ9THC浓度没有年龄或品系差异；然而，129S6/SvEv小鼠大脑中Δ9THC的浓度显著高于FVB小鼠。此外，与5支香烟相比，3支香烟产生的血浆中11-COOH-THC浓度显著较低，尽管Δ9THC或11-OH-THC的血浆或大脑浓度中剂量差异不明显。在所有实验中，雌性血浆中11-COOH-THC的水平高于雄性。结果揭示了Δ9THC药代动力学中存在明显的性别差异，并为未来使用小鼠模拟吸食大麻的药效学研究奠定了基础。
