Is tolerance to delta-9-THC cellular or metabolic? The subcellular distribution of delta-9-tetrahydrocannabinol and its metabolites in brains of tolerant and non-tolerant rats.

Rats were injected intraperitoneally once every 12 h with 10 mg/kg delta-9-THC and the time course of the depressant effect was determined after one and nine injections. The motor activity of naive rats was maximally depressed between 1 and 4 h and returned to control levels 8 h after treatment. After nine injections, the maximum intensity of the depressant effect was not different from that after one injection but had completely disappeared at an earlier time point (4 h p.i.) indicating the development of tolerance to the duration of effect on motor activity. The subcellular distribution studies in brains of tolerant and non-tolerant rats indicated that an accelerated shift in the concentrations of delta-9-THC and 11-OH-delta-9-THC towards highly polar metabolites in the brains, rather than an increased elimination of these cannabinoids or decreased sensitivity of the brain may be responsible for the development of tolerance to delta-9-THC.