SR 141716 (Rimonabant) precipitates withdrawal in marijuana-dependent mice

Repeated marijuana use is known to lead to physical dependence in humans; however, its dependence liability has yet to be adequately assessed in laboratory animals. The goals of the present study were to: assess whether the CB1 antagonist SR 141716 (rimonabant) precipitates withdrawal in mice that had been repeatedly exposed to marijuana smoke, and to compare these precipitated withdrawal effects to those elicited following intravenous administration of its chief psychoactive component Δ9-tetrahydrocannabinol (Δ9-THC). SR 141716 elicited a significant increase in paw tremors in mice that were repeatedly dosed with either marijuana or Δ9-THC. Unexpectedly, the blood and brain concentrations of Δ9-THC following marijuana exposure were considerably lower than those found following Δ9-THC injection when comparing an equivalent magnitude of paw tremors in both conditions. Finally, Δ9-THC dose-dependently alleviated SR 141716-induced paw tremors in marijuana-dependent mice, but marijuana itself failed to reverse the precipitated withdrawal effect. It is likely that marijuana exposure generated insufficient Δ9-THC brain levels (i.e., 203 ± 19 ng/g) to reverse the withdrawal signs compared with the brain levels following intravenous injection (i.e., 1862 ±82 ng/g). These findings taken together indicate that mice exposed repeatedly to marijuana smoke exhibit similar precipitated withdrawal effects as Δ9-THC-injected mice.