Pharmacokinetic and motivational properties of vaporized cannabis in mice

项目摘要 大麻在美国几个州的合法化增加了更好地了解其 对身体、大脑和行为的影响。啮齿动物模型在这方面特别有价值，因为它们 提供对外部变量的精确控制，并且啮齿动物的大脑显示出结构和功能同源性 与人类大脑中与药物依赖和情绪行为相关的区域。然而， 建立更接近人类大麻使用模式的临床前动物模型， 我们研究现实世界大麻使用和滥用的生物后果的能力。处理这个关键 屏障，麦克劳克林实验室最近开发并验证了一种新的蒸汽吸入模型 用于在大鼠中以实验者控制或响应视情况的方式递送大麻提取物。虽然 这个模型为研究大麻寻求行为提供了宝贵的机会， 在大鼠中可用的遗传工具包阻碍了细胞类型和电路特异性方法的使用。相反地， 老鼠身上的尖端遗传工具使它们成为研究大麻如何使用的有吸引力的模型。 影响大脑和周围的各种生物学终点。要实现一个生态上有效的鼠标 大麻使用模型，我们必须首先建立最佳的大麻蒸汽剂量参数， 年龄、性别和品系，并确定小鼠自我给药的可行性，以确保未来的可复制性 问题研究因此，这项R21建议的目的是建立这种近交系和非近交系使用大麻的模式， 雄性和雌性小鼠在青春期和成年期的远系繁殖。在目标1中，我们将使用 实验者控制的大麻蒸汽递送方法，以确定药物动力学和行为 大麻蒸汽暴露对两种性别的近交系（C57 BL/6）和远交系（CD-1）小鼠品系的影响 在青春期和成年期。在目标2中，我们将使用这些给药参数来确定 大麻蒸汽支持两种性别、年龄和品系的小鼠的稳定的大麻寻求行为。 总之，这些目标采用了技术创新的方法，并将建立重要的工作参数， 将提供严格的药代动力学和大麻模拟效应的急性暴露， 汽化的大麻资助这项R21提案将是在小鼠中产生必要的试验数据的第一步 这将支持我们多学科研究小组未来的许多合作提案， （McLaughlin，Delevich，and Hayashi）.此外，它将为WSU的其他人提供一个有价值的起点 社区和其他社区对在小鼠中采用大麻蒸气递送方法感兴趣。

PROJECT SUMMARY The legalization of cannabis in several states across the US has increased the need to better understand its effects on the body, brain, and behavior. Rodent models are particularly valuable in this respect because they provide precise control over external variables and the rodent brain shows structural and functional homology with the human brain in regions relevant to drug dependence and emotional behavior. However, obstacles to establishing preclinical animal models that more closely resemble human patterns of cannabis use have limited our ability to study the biological consequences of real-world cannabis use and misuse. To address this critical barrier in the field, the McLaughlin Laboratory recently developed and validated a novel vapor inhalation model for delivering cannabis extracts in an experimenter-controlled or response-contingent manner in rats. Although this model has provided valuable opportunities for examining cannabis-seeking behavior, the relatively limited genetic toolkit available in rats has hindered the use of cell type- and circuit-specific approaches. Conversely, the cutting-edge genetic tools available in mice make them an attractive model for studying how cannabis use impacts various biological endpoints in the brain and periphery. To implement an ecologically valid mouse model of cannabis use, we must first establish optimal cannabis vapor dosing parameters across conditions of age, sex, and strain and determine the feasibility of self-administration in mice to ensure replicability for future studies. Thus, the objective of this R21 proposal is to establish this model of cannabis use in inbred and outbred strains of male and female mice during adolescence and adulthood. In Aim 1, we will use an experimenter-controlled cannabis vapor delivery approach to determine the pharmacokinetic and behavioral effects of cannabis vapor exposure in inbred (C57BL/6) and outbred (CD-1) mouse strains of both sexes during adolescence and adulthood. In Aim 2, we will use these dosing parameters to determine whether cannabis vapor supports stable cannabis-seeking behaviors in mice of both sexes, ages, and strains. Together, these aims employ a technically innovative approach and will establish vital working parameters that will afford rigorous characterization of the pharmacokinetic and cannabimimetic effects of acute exposure to vaporized cannabis. Funding this R21 proposal will be the first step in generating necessary pilot data in mice that will support many future collaborative proposals from our multidisciplinary group of investigators (McLaughlin, Delevich, and Hayashi). Moreover, it will provide a valuable starting point for others in the WSU community and beyond that are interested in employing cannabis vapor delivery approaches in mice.