Tolerance to the effects of ? 9-tetrahydrocannabinol in mice on intestinal motility, temperature and locomotor activity

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Abstract
The onset and duration of tolerance to three effects of δ 9-tetrahydrocannabinol (δ 9-THC) given orally to mice were compared. The effects of δ 9-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 δ 9-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 δ 9-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 δ 9-THC.