Pharmacokinetic factors in sex differences in Δ 9-tetrahydrocannabinol-induced behavioral effects in rats

Abstract

Cannabinoids have been shown to produce greater behavioral effects in female than in male rats. Sex differences in the metabolism of Δ 9-tetrahydrocannabinol (Δ 9-THC) have also been demonstrated in one study. The goal of this study was to determine if sex differences in Δ 9-THC disposition or metabolism could explain sex differences in Δ 9-THC-induced behavioral effects. [ 3 H ]-Δ 9-THC was administered intraperitoneally (i.p.) to rats and the presence of [ 3 H ]-Δ 9-THC and metabolites in serum and brain tissue were compared at multiple times post-injection in male versus female rats. Serum levels of Δ 9-THC and its metabolites were similar in males and females. In brain tissue, [ 3 H ]-Δ 9-THC levels also were similar in males and females. In contrast, levels of Δ 9-THC metabolites in brain tissue, including 11-hydroxy-Δ 9-THC, the major active metabolite, were higher in females than in males. To further investigate if greater production of active metabolites by females explained the greater Δ 9-THC-induced behavioral effects observed in females, i.p. Δ 9-THC-induced antinociception (50 °C warm water tail withdrawal assay) and catalepsy (bar test) were compared in male and female rats following pretreatment with saline or SKF525A, a cytochrome P450 inhibitor. SKF525A did not affect basal responding in the tail withdrawal assay or bar test in either sex. SKF525A significantly attenuated Δ 9-THC-induced antinociception only in females. A similar sex difference was observed in the effects of SKF525A on Δ 9-THC-induced catalepsy. These results suggest that the greater levels of active Δ 9-THC metabolites produced by females contribute to greater behavioral effects of Δ 9-THC in female compared to male rats.