Pharmacokinetic and motivational properties of vaporized cannabis in mice

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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.