Acute and Repeated Administration of SR141716A on Δ 9 ‐tetrahydrocannabinol’s Effects

Acute administration of the cannabinoid CB1 receptor antagonist SR141716A has been shown to antagonize the effects of cannabinoid CB1 receptor agonists such as Δ9-tetrahydrocannabinol (Δ9-THC). The purpose of this study was to determine the effects of repeated administration of SR141716A on Δ9-THC-induced hypothermia, locomotor inhibition, and antinociception. Male ICR mice were dosed twice daily for 6.5 days (i.e., 13 injections) with SR141716A (10 or 30 mg/kg, s.c.) or vehicle (VEH). On the 8th day, mice were dosed with SR141716A (10mg/kg, i.v.) or VEH, and 10 min later, with either Δ9-THC (3 mg/kg or 10 mg/kg, i.v.) or VEH. Then, they were tested in the in vivo assays. As previously reported, the acute administration of SR141716A reversed the cannabinoid effects of Δ9-THC. Repeated administration of 10 mg/kg SR141716A did not alter its antagonism of Δ9-THC’s effects nor did it affect responding in mice that received Δ9-THC and VEH on the 8th day. These results suggest that tolerance to SR141716A’s antagonistic effects did not develop. Although repeated dosing with 30 mg/kg SR141716A resulted in a similar absence of cannabinoid effects in mice that received 10 mg/kg SR141716A and Δ9-THC on day 8, injection with Δ9-THC and VEH also failed to produce full cannabinoid effects. By day 10, partial recovery was observed. While pharmacokinetic factors have not been ruled out, it is also possible that repeated treatment with a higher dose of SR141716A may have decreased the sensitivity of the endocannabinoid system to Δ9-THC. Supported by NIDA grants DA-03672, DA-09789, and DA-08904.