Abstract
Introduction: Studies in rodent models have shown that adolescent exposure to Δ(9)-THC, the psychotropic constituent of cannabis, produces long-lasting alterations in brain function and behavior. However, our understanding of how age and sex might influence the distribution and metabolism of THC in laboratory rodents is still incomplete. In the present report, we provide a comparative analysis of the pharmacokinetic (PK) properties of THC in adolescent and adult rats of both sexes, and outline several dissimilarities across these groups. Materials and Methods: A single (acute) or 2-week daily (subchronic) administration of THC (0.5 or 5 mg/kg, acute; 5 mg/kg, subchronic; intraperitoneal) was given to adolescent (33-day-old, acute; 30-44-day-old, subchronic) and young adult (70-day-old, acute only) male and female rats. THC and its first-pass metabolites-11-hydroxy-Δ(9)-THC (11-OH-THC) and 11-nor-9-carboxy-Δ(9)-THC (11-COOH-THC)-were quantified in plasma and brain tissue using a selective isotope-dilution liquid chromatography/tandem mass spectrometry assay. Changes in body temperature were measured using abdominally implanted microchips. Biotransformation of THC to its metabolites using freshly prepared liver microsomes was assessed. Results: At the acute 5 mg/kg dose, maximal plasma concentrations of THC were twice as high in adult than in adolescent rats. Conversely, in adults, brain concentrations and brain-to-plasma ratios for THC were substantially lower (25-50%) than those measured in adolescents. Similarly, plasma and brain concentrations of THC metabolites were higher in adolescent male rats compared with adult males. Interestingly, plasma and brain concentrations of the psychoactive THC metabolite 11-OH-THC were twofold to sevenfold higher in female animals of both ages compared with males. Moreover, liver microsomes from adolescent males and adolescent and adult females converted THC to 11-OH-THC twice as fast as adult male microsomes. A dose-dependent hypothermic response to THC was observed in females with 0.5 and 5 mg/kg THC, whereas only the highest dose elicited a response in males. Finally, subchronic administration of THC during adolescence did not significantly affect the drug's PK profile. Conclusions: The results reveal the existence of multiple age and sex differences in the distribution and metabolism of THC in rats, which might influence the pharmacological response to the drug.