C M Ruiz1, A Torrens2, V Lallai1, E Castillo1, L Manca1, M X Martinez1, D N Justeson1, C D Fowler1, D Piomelli2, S V Mahler3. 1. Department of Neurobiology & Behavior, University of California Irvine, 2205 McGaugh Hall, Irvine, CA, 92697, USA. 2. Department of Anatomy & Neurobiology, University of California Irvine, 1244 Gillespie Hall, Irvine, CA, 92697, USA. 3. Department of Neurobiology & Behavior, University of California Irvine, 2205 McGaugh Hall, Irvine, CA, 92697, USA. mahlers@uci.edu.
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.
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.
Authors: Angeline J Dukes; James P Fowler; Valeria Lallai; Anna N Pushkin; Christie D Fowler Journal: Nicotine Tob Res Date: 2020-07-16 Impact factor: 4.244
Authors: Timothy G Freels; Lydia N Baxter-Potter; Janelle M Lugo; Nicholas C Glodosky; Hayden R Wright; Samantha L Baglot; Gavin N Petrie; Zhihao Yu; Brian H Clowers; Carrie Cuttler; Rita A Fuchs; Matthew N Hill; Ryan J McLaughlin Journal: J Neurosci Date: 2020-01-17 Impact factor: 6.167