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-tetrahydrocanna binol (Delta(9)-THC) was studied in an effort to determine the role that le ngth of dosing may have in the onset and maintenance of tolerance. Mice wer e chronically treated with either vehicle or 10 mg/kg of Delta(9)-THC subcu taneously twice a day. The mice were tested 24 h after the last injection f or tolerance as assessed by the production of antinociception and suppressi on of spontaneous activity. Tolerance was first observed after three inject ions 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, respective ly. 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 o f tolerance. The time course for the recovery from Delta(9)-THC-induced tol erance was also determined with a separate group of animals. Mice were dose d 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 witho ut drug treatment the mice exhibited a 7.5-fold and 2.3-fold degree of tole rance 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 me asure of hypoactivity. No tolerance was observed for the measure of antinoc iception after 11.5 days without drug treatment. This time course indicates that the mechanisms responsible for either the production or maintenance o f tolerance differ between the measures of antinociception and suppression of spontaneous activity. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.