Delta-9-tetrahydrocannabinol vaping in mice: pharmacokinetic validation and structural, metabolic and behavioural outcomes

Introduction

The increasing prevalence of cannabis vaping raises important translational concerns, as most preclinical studies rely on intraperitoneal (i.p.) administration, poorly reflecting human exposure routes. Delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, has been associated with neuroinflammatory processes, structural brain changes, and cognitive impairment. Conversely, cannabidiol (CBD) has shown neuroprotective effects, but its modulatory role under inflammatory conditions remains poorly characterized. Pharmacokinetic validation of vaporized THC models and characterization of their neurobiological outcomes are therefore essential for translational cannabinoid research.

Objectives

O1. To validate a THC vaping model by comparing serum concentrations following vaping and i.p. administration at two time points. O2. To assess brain volumetric changes. O3. To explore neurometabolic changes using single-voxel magnetic resonance spectroscopy (MRS). O4. To evaluate neurobehavioral outcomes in locomotion and short- and long-term memory.

Methods

Male C57BL/6 mice were exposed to THC vaping (100 mg/mL, 30 min/day) or received i.p. THC injections (10 mg/kg) for 15 days. Serum THC concentrations were quantified after acute and chronic exposure. A separate cohort received intranasal LPS (two doses of 5 mg/kg, 24 h apart) to induce acute lung inflammation. Following LPS challenge, mice were treated with CBD (10 mg/kg for 12 days). Brain structural volumes were assessed using region-of-interest segmentation of MRI images, and brain metabolite concentrations were determined using LCModel software. Behavioral testing included the open field test and the novel object recognition test (NOR). Statistical analyses were performed using GraphPadPrism and SPSS.

Results

Serum THC levels were higher following acute than chronic exposure in both administration routes, with reduced interindividual variability observed under chronic conditions. Acute vapor inhalation yielded higher serum THC concentrations than acute i.p. administration, whereas chronic levels were comparable between routes, supporting pharmacokinetic equivalence of the vaporized model under sustained exposure.

MRI volumetric segmentation revealed increased dorsal hippocampal volume following THC exposure, which was not attenuated by CBD. Ventricular volumes were enlarged by LPS, with CBD partially reversing this effect, mainly in air-exposed animals. Cerebellar volume increased in all treated mice, regardless of treatment condition.

MRS analysis revealed no significant metabolic changes in air-exposed animals. However, in THC-exposed animals, some metabolites differed significantly across groups (e.g., GPC), with CBD increasing and LPS reducing concentrations, suggesting altered membrane phospholipid metabolism under inflammation.

In the open field test, THC induced hyper-locomotion, which was attenuated by CBD. LPS markedly reduced rearing behavior only in air-exposed groups, an effect that was improved by CBD. In the NOR test, LPS impaired short-term exploration without reversal by CBD. In long-term memory, CBD showed an overall rescue effect on exploratory behavior in THC-LPS-exposed animals.

Conclusions

Under chronic exposure, THC vaping produces serum levels comparable to i.p. administration, supporting its translational validity in cannabinoid research. Progressive reductions in circulating THC levels suggest the development of metabolic tolerance. THC and CBD differentially modulate hippocampal and ventricular volumes, metabolic profiles, and behavioral outcomes, with LPS-induced inflammation acting as a critical moderating factor. These findings support the use of vaporized cannabinoid models and highlight the complex interplay between cannabinoids and peripheral inflammation in shaping brain structural and functional alterations.

References

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