Time course for the induction and maintenance of tolerance to Delta(9)-tetrahydrocannabinol in mice

The time course for the development of tolerance to delta-9-tetrahydrocannabinol (Delta(9)-THC) was studied in an effort to determine the role that length of dosing may have in the onset and maintenance of tolerance. Mice were chronically treated with either vehicle or 10 mg/kg of Delta(9)-THC subcutaneously twice a day. The mice were tested 24 h after the last injection for tolerance as assessed by the production of antinociception and suppression of spontaneous activity. Tolerance was first observed after three injections of Delta(9)-THC (1.5 days) resulting in a 7-fold and 23-fold decrease in potency for the measures of antinociception and hypoactivity, respectively. Seven injections of Delta(9)-THC (3.5 days of dosing) resulted in a 12-fold and 36-fold decrease in potency, respectively, while 13 injections of Delta(9)-THC (6.5 days of dosing) produced a 6.2-fold and 9.8-fold degree of tolerance. The time course for the recovery from Delta(9)-THC-induced tolerance was also determined with a separate group of animals. Mice were dosed for 6.5 days with 10 mg/kg of Delta(9)-THC and were not tested until 4.5, 7.5, and 11.5 days after cessation of drug treatment. After 4.5 days without drug treatment the mice exhibited a 7.5-fold and 2.3-fold degree of tolerance as measured by antinociception and hypoactivity, respectively. After 7. 5 days without drug treatment a 3.4-fold degree of tolerance remained for the measure of antinociception, while no tolerance was detected for the measure of hypoactivity. No tolerance was observed for the measure of antinociception after 11.5 days without drug treatment. This time course indicates that the mechanisms responsible for either the production or maintenance of tolerance differ between the measures of antinociception and suppression of spontaneous activity.