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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要美国多个州的大麻合法化增加了更好地了解大麻的必要性对身体、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，啮齿动物大脑显示结构和功能同源性与人脑中与药物依赖和情绪行为相关的区域。然而，障碍建立更接近人类大麻使用模式的临床前动物模型有限我们研究现实世界大麻使用和滥用的生物学后果的能力。为了解决这个关键问题麦克劳克林实验室最近开发并验证了一种新型蒸气吸入模型用于以实验者控制或反应相关的方式向大鼠输送大麻提取物。虽然该模型为研究大麻寻求行为提供了宝贵的机会，这种行为相对有限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。反过来，小鼠身上可用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外周的各种生物终点。实现生态有效的小鼠大麻使用模型中，我们必须首先在各种条件下建立最佳的大麻蒸气剂量参数年龄、性别和应变，并确定小鼠自我给药的可行性，以确保未来的可复制性研究。因此，该 R21 提案的目标是建立近交和近交大麻使用模式雄性和雌性小鼠在青春期和成年期进行近亲繁殖。在目标 1 中，我们将使用实验者控制的大麻蒸气输送方法以确定药代动力学和行为大麻蒸气暴露对近交系 (C57BL/6) 和远交系 (CD-1) 两性小鼠品系的影响在青春期和成年期。在目标 2 中，我们将使用这些剂量参数来确定是否大麻蒸气支持不同性别、年龄和品系的小鼠稳定的大麻寻求行为。这些目标共同采用了技术创新方法，并将建立重要的工作参数，将提供急性暴露的药代动力学和大麻模拟效应的严格表征蒸发的大麻。资助这项 R21 提案将是生成必要的小鼠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（麦克劳克林、德莱维奇和林）。此外，它将为 WSU 的其他人提供一个宝贵的起点社区及其他领域有兴趣在小鼠身上采用大麻蒸气输送方法。