Pharmacokinetic and motivational properties of vaporized cannabis in mice

汽化大麻在小鼠体内的药代动力学和激励特性

• 批准号: 10569883
• 负责人: Kristen Marie Delevich
• 金额: $ 22.95万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569883
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Age; Animal Model; Animals; Behavior; Behavioral; Biological; Biological Factors; Brain; Cannabinoids; Cannabis; Catheterization; Cells; Cognitive; Communities; Consumption; Cues; Data; Discrimination; Dose; Drug Addiction; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Ensure; Ethanol Metabolism; Explosion; Exposure to; Female; Fentanyl; Flowers; Formulation; Funding; Funding Opportunities; Future; Genetic; Genome; Goals; Human; Inbreeding; Inhalation; Injections; Intake; Intraperitoneal Injections; Intravenous; Laboratories; Lead; Long-Term Effects; Lung; Measures; Methods; Modeling; Monitor; Motivation; Mouse Strains; Mus; National Institute of Drug Abuse; Nicotine; Pattern; Pharmaceutical Preparations; Physiological; Plants; Plasma; Population; Pre-Clinical Model; Preparation; Property; Rattus; Regimen; Reinforcement Schedule; Reproduction; Research Personnel; Rewards; Rodent; Rodent Model; Route; Self Administration; Smoke; Standardization; Study models; Testing; Tetrahydrocannabinol; Validation; addiction; alcohol and other drug; brain behavior; cannabimimetics; cell type; cost; design; emotional behavior; feasibility testing; fetal marijuana exposure; genetic manipulation; innovation; insight; interest; intravenous injection; male; marijuana legalization; marijuana use; marijuana user; mouse model; multidisciplinary; novel; pharmacokinetics and pharmacodynamics; pre-clinical; response; sex; synthetic cannabinoid; tool; vapor; vaporization

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.

项目总结 美国几个州的大麻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，啮齿类动物的大脑显示出结构和功能的同源性 人类大脑中与药物依赖和情绪行为相关的区域。然而，阻碍 建立更接近人类大麻使用模式的临床前动物模型是有限的 我们研究真实世界中大麻使用和滥用的生物学后果的能力。要解决这一关键问题 ，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 用于以实验者控制或反应应急的方式在大鼠体内传递大麻提取物。虽然 这一模型为研究大麻寻觅行为提供了宝贵的机会，相对有限 大鼠可用的遗传工具箱阻碍了细胞类型和电路特异性方法的使用。相反， 在老鼠身上可获得的尖端遗传工具使它们成为研究大麻使用方式的一个有吸引力的模型 影响大脑和外周的各种生物终点。实现一种生态上有效的鼠标 对于大麻使用的模型，我们必须首先建立在以下条件下的最佳大麻蒸气剂量参数 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 学习。因此，这项R21提案的目标是在近亲交配和 青春期和成年期雄性和雌性小鼠的杂交品系。在目标1中，我们将使用 实验者控制的大麻蒸气给药方法测定药代动力学和行为学 大麻蒸气暴露对近交系(C57BL/6)和近交系(CD-1)小鼠的影响 在青春期和成年期。在目标2中，我们将使用这些剂量参数来确定 大麻蒸气支持不同性别、年龄和品系的小鼠稳定的大麻寻找行为。 总之，这些目标采用了一种技术创新的方法，并将建立关键的工作参数，以 将提供对急性接触大麻的药代动力学和拟大麻效应的严格表征 蒸发的大麻。资助R21提案将是在MICE中生成必要的试验数据的第一步 这将支持我们多学科调查小组未来的许多合作建议 (McLaughlin，Dlevich和Hayashi)此外，它将为WSU中的其他人提供一个宝贵的起点 社区和其他社区对在小鼠身上使用大麻蒸气输送方法感兴趣。