Ravula Abhigyan, Chandasana Hardik, Jagnarine Darin, Wall Shannon C, Setlow Barry, Febo Marcelo, Bruijnzeel Adriaan W, Derendorf Hartmut
Department of Pharmaceutics, University of Florida, Gainesville, Florida.
Department of Psychiatry, University of Florida, Gainesville, Florida.
Cannabis Cannabinoid Res. 2019 Dec 6;4(4):240-254. doi: 10.1089/can.2019.0049. eCollection 2019.
Cannabis is the most widely used illicit drug in the US, and cannabis use among young adults continues to rise. Previous studies have shown that chronic administration of delta 9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, induces dependence in animal models. Because smoking is the most frequent route of THC self-administration, it is critical to investigate the effects of cannabis smoke inhalation. The goal of the current study was to develop a rat model to characterize the pharmacokinetics (PKs) of THC after cannabis smoke inhalation, and to determine if chronic cannabis smoke inhalation leads to the development of cannabis dependence. For the PK study, male Wistar rats were administered THC intravenously (1 mg/kg) or exposed to smoke from 5 or 10 sequentially smoked cannabis cigarettes (5.3% THC) in an automated smoking machine. Plasma samples were collected from 10 min to 10 hours post smoke exposure (or intravenous administration) and analyzed using liquid chromatography-mass spectrometry to characterize the PK of THC. A three-compartment PK model was used to characterize the PKs. In a separate study, three groups of male Wistar rats were trained in an intracranial self-stimulation (ICSS) procedure, and exposed to smoke from burning 5 or 10 cannabis cigarettes (or clean air control conditions), 5 days/week for 4 weeks. Across exposure days, the change from baseline in ICSS thresholds for cannabis smoke-exposed groups was significantly lower and response latencies were significantly faster in the cannabis smoke-exposed groups compared to controls, suggesting that chronic cannabis smoke exposure has rewarding properties. Acute administration of the CB1 receptor antagonist rimonabant (0.3, 1.0, 3.0 mg/kg) induced a dose-dependent increase in ICSS thresholds in the smoke-exposed rats, suggestive of dependence and withdrawal. Finally, an effect compartment PK-pharmacodynamic model was used to describe the relationship between THC concentrations and changes in ICSS thresholds after cannabis smoke exposure.
大麻是美国使用最广泛的非法药物，并且年轻人中的大麻使用量持续上升。先前的研究表明，长期给予大麻的主要精神活性成分Δ9-四氢大麻酚（THC）会在动物模型中诱发依赖性。由于吸烟是THC自我给药最常见的途径，因此研究吸入大麻烟雾的影响至关重要。当前研究的目的是建立一个大鼠模型，以表征吸入大麻烟雾后THC的药代动力学（PKs），并确定长期吸入大麻烟雾是否会导致大麻依赖的形成。对于PK研究，将雄性Wistar大鼠静脉注射THC（1mg/kg），或在自动吸烟机中暴露于5支或10支依次吸食的大麻香烟（THC含量为5.3%）所产生的烟雾中。在烟雾暴露（或静脉注射）后10分钟至10小时收集血浆样本，并使用液相色谱-质谱法进行分析，以表征THC的PK。使用三室PK模型来表征PKs。在另一项研究中，三组雄性Wistar大鼠接受颅内自我刺激（ICSS）程序训练，并暴露于燃烧5支或10支大麻香烟所产生的烟雾中（或清洁空气对照条件下），每周5天，共4周。在整个暴露期间，与对照组相比，大麻烟雾暴露组的ICSS阈值相对于基线的变化显著更低，且反应潜伏期显著更快，这表明长期暴露于大麻烟雾具有奖赏特性。急性给予CB1受体拮抗剂利莫那班（0.3、1.0、3.0mg/kg）会使烟雾暴露大鼠的ICSS阈值出现剂量依赖性升高，提示存在依赖性和戒断反应。最后，使用效应室PK-药效学模型来描述吸入大麻烟雾后THC浓度与ICSS阈值变化之间的关系。
