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Time course for the induction and maintenance of tolerance to Delta(9)-tetrahydrocannabinol in mice
by
Bass CE, Martin BR
ABSTRACT
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.
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