Tolerance to the effect of delta9-tetrahydrocannabinol in mice on intestinal motility, temperature and locomotor activity.

The onset and duration of tolerance to three effects of delta9-tetrahydrocannabinol (delta9-THC) given orally to mice were compared. The effects of delta9-THC studied were: hypothermia, the depression of intestinal motility and the effect on spontaneous locomotor activity. When mice were dosed and tested at 24 hrs intervals it was apparent that tolerance was complete to its hypothermic and locomotor depressant effects after the first doses and to depression of intestinal motility after the fourth dose. Duration of tolerance also differed so that the normal hypothermic response had returned after 12 dose-free days, but not after 5 drug-free days; the effect on locomotor activity had returned within 4 days; and apparent partial tolerance to the depressant effect of an acute challenging dose of delta9-THC on intestinal motility still existed after 19 dose-free days. It is apparent that the time of onset and the duration of tolerance to delta9-THC in mice showed a different pattern in the three parameters studied. It seems unlikely therefore that any one mechanism, such as metabolic tolerance, explains all the results observed and that several mechanisms should be explored to explain the phenomenon of tolerance to delta9-THC.