TY - JOUR T1 - Comparative Pharmacokinetics of Δ<sup>9</sup>-Tetrahydrocannabinol in Adolescent and Adult Male Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 151 LP - 160 DO - 10.1124/jpet.120.265892 VL - 374 IS - 1 AU - Alexa Torrens AU - Valentina Vozella AU - Hannah Huff AU - Brandon McNeil AU - Faizy Ahmed AU - Andrea Ghidini AU - Stephen V. Mahler AU - Marilyn A. Huestis AU - Aditi Das AU - Daniele Piomelli Y1 - 2020/07/01 UR - http://jpet.aspetjournals.org/content/374/1/151.abstract N2 - We investigated the pharmacokinetic properties of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of cannabis, in adolescent and adult male mice. The drug was administered at logarithmically ascending doses (0.5, 1.6, and 5 mg/kg, i.p.) to pubertal adolescent (37-day-old) and adult (70-day-old) mice. Δ9-THC and its first-pass metabolites—11-hydroxy-Δ9-THC and 11-nor-9-carboxy-Δ9-THC (11-COOH-THC)—were quantified in plasma, brain, and white adipose tissue (WAT) using a validated isotope-dilution liquid chromatography/tandem mass spectrometry assay. Δ9-THC (5 mg/kg) reached 50% higher circulating concentration in adolescent mice than in adult mice. A similar age-dependent difference was observed in WAT. Conversely, 40%–60% lower brain concentrations and brain-to-plasma ratios for Δ9-THC and 50%–70% higher brain concentrations for Δ9-THC metabolites were measured in adolescent animals relative to adult animals. Liver microsomes from adolescent mice converted Δ9-THC into 11-COOH-THC twice as fast as adult microsomes. Moreover, the brains of adolescent mice contained higher mRNA levels of the multidrug transporter breast cancer resistance protein, which may extrude Δ9-THC from the brain, and higher mRNA levels of claudin-5, a protein that contributes to blood-brain barrier integrity. Finally, administration of Δ9-THC (5 mg/kg) reduced spontaneous locomotor activity in adult, but not adolescent, animals. The results reveal the existence of multiple differences in the distribution and metabolism of Δ9-THC between adolescent and adult male mice, which might influence the pharmacological response to the drug.SIGNIFICANCE STATEMENT Animal studies suggest that adolescent exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the intoxicating constituent of cannabis, causes persistent changes in brain function. These studies generally overlook the impact that age-dependent changes in the distribution and metabolism of the drug might exert on its pharmacological effects. This report provides a comparative analysis of the pharmacokinetic properties of Δ9-THC in adolescent and adult male mice and outlines multiple functionally significant dissimilarities in the distribution and metabolism of Δ9-THC between these two age groups. ER -