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Pharmacokinetic and pharmacodynamic properties of aerosolized (“vaped”) THC in adolescent male and female rats

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Abstract

Rationale

Adolescent exposure to ∆9-tetrahydrocannabinol (THC), the psychotropic constituent of cannabis, might affect brain development, and in rodent models leads to long-term behavioral and physiological alterations. Yet, the basic pharmacology of this drug in adolescent rodents, especially when ingested via ecologically relevant routes like aerosol inhalation, commonly referred to as “vaping,” is still poorly characterized. Moreover, sex differences exist in THC metabolism, kinetics, and behavioral effects, but these have not been rigorously examined after vapor dosing in adolescents.

Objectives

We investigated the pharmacokinetics and pharmacodynamics of aerosolized THC (30 min inhalation exposure, 25 or 100 mg/ml) in adolescent Wistar rats of both sexes.

Methods

Liquid chromatography/mass spectrometry analysis of THC and its major metabolites was conducted on blood plasma and brain tissue at 5, 30, 60, and 120 min following a 30-min aerosol dosing session. Effects on activity in a novel environment for 120 min after aerosol, and temperature, were measured in separate rats.

Results

We found sex-dependent differences in the pharmacokinetics of THC and its active (11-OH-THC) and inactive (11-COOH-THC) metabolites in the blood and brain, along with dose- and sex-dependent effects on anxiety-like and exploratory behaviors; namely, greater 11-OH-THC levels accompanied by greater behavioral effects in females at the low dose but similar hypothermic effects in both sexes at the high dose.

Conclusions

These results provide a benchmark for dosing adolescent rats with aerosolized (or “vaped”) THC, which could facilitate adoption by other labs of this potentially human-relevant THC exposure model to understand cannabis effects on the developing brain.

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Acknowledgements

We thank Maury Cole at La Jolla Alcohol Research, Inc., for advice on vapor equipment design.

Funding

These studies were funded by NIH P50 DA044118 and R01 DA051831 and the State of California Tobacco-Related Disease Research Program grants T31IR1767, T29IR0618, and T30FT0967.

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Authors and Affiliations

  1. Department of Neurobiology & Behavior, University of California Irvine, 2205 McGaugh Hall, Irvine, CA, 92697, USA

    C. M. Ruiz, V. Lallai, E. Castillo, L. Manca, M. X. Martinez, D. N. Justeson, C. D. Fowler & S. V. Mahler

  2. Department of Anatomy & Neurobiology, University of California Irvine, 1244 Gillespie Hall, Irvine, CA, 92697, USA

    A. Torrens & D. Piomelli

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  1. C. M. Ruiz
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  2. A. Torrens
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  3. V. Lallai
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  4. E. Castillo
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  5. L. Manca
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  6. M. X. Martinez
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  7. D. N. Justeson
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  8. C. D. Fowler
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  9. D. Piomelli
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  10. S. V. Mahler
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Correspondence to S. V. Mahler.

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Ruiz, C.M., Torrens, A., Lallai, V. et al. Pharmacokinetic and pharmacodynamic properties of aerosolized (“vaped”) THC in adolescent male and female rats. Psychopharmacology 238, 3595–3605 (2021). https://doi.org/10.1007/s00213-021-05976-8

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  • DOI: https://doi.org/10.1007/s00213-021-05976-8

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