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: Cannabinoids have been shown to produce greater behavioral effects in female than in male rats. Sex differences in the metabolism of [DELTA]9-tetrahydrocannabinol ([DELTA]9-THC) have also been demonstrated in one study. The goal of this study was to determine if sex differences in [DELTA]9-THC disposition or metabolism could explain sex differences in [DELTA]9-THC-induced behavioral effects. [3H]-[DELTA]9-THC was administered intraperitoneally (i.p.) to rats and the presence of [3H]-[DELTA]9-THC and metabolites in serum and brain tissue were compared at multiple times post-injection in male versus female rats. Serum levels of [DELTA]9-THC and its metabolites were similar in males and females. In brain tissue, [3H]-[DELTA]9-THC levels also were similar in males and females. In contrast, levels of [DELTA]9-THC metabolites in brain tissue, including 11-hydroxy-[DELTA]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 [DELTA]9-THC-induced behavioral effects observed in females, i.p. [DELTA]9-THC-induced antinociception (50[degrees]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 [DELTA]9-THC-induced antinociception only in females. A similar sex difference was observed in the effects of SKF525A on [DELTA]9-THC-induced catalepsy. These results suggest that the greater levels of active [DELTA]9-THC metabolites produced by females contribute to greater behavioral effects of [DELTA]9-THC in female compared to male rats.

(C) 2004Elsevier, Inc.