CB1 receptor antagonist precipitates withdrawal in mice exposed to Δ9- tetrahydrocannabinol

Although tolerance to cannabinoids has been well established, the question of cannabinoid dependence had been very con-troversial until the discovery of a cannabinoid antagonist, SR141716A. The objective of this study was to develop and characterize a mouse model of precipitated withdrawal indica-tive of cannabinoid dependence. Using a dosing regimen known to produce pharmacological and behavioral tolerance, mice were treated with D9-tetrahydrocannabinol (D9-THC) twice a day for 1 wk. SR141716A administration after the last D9-THC injection promptly precipitated a profound withdrawal syndrome. Typical withdrawal behavior was an increase in paw tremors and head shakes that was accompanied with a de-crease in normal behavior such as grooming and scratching. Of the three D9-THC regimens tested, daily D9-THC injections of 10 and 30 mg/kg produced the greatest number of paw tremors and head shakes and the least number of grooms after chal-lenge with SR141716A. Precipitated withdrawal was apparent after 2, 3, 7 and 14 days of treatment based on an increase in paw tremors in D9-THC-treated mice as compared with vehi-cle-treated mice. These findings are consistent with SR141716A-precipitated withdrawal in rats. Moreover, these results suggest that mice are a viable model for investigating dependence to cannabinoids. With the extensive use of marijuana recreationally and its promotion as a therapeutic agent for the treatment of emesis, pain, and loss of appetite, the adverse consequences of chronic exposure become increasingly important. As a result, tolerance and dependence to cannabinoids have generated renewed interest. Tolerance is known to develop to most of the pharmacological effects of D9-THC that included antino-ciception, hypothermia, depression of locomotor activity, cat-alepsy, anticonvulsant activity, ataxia, hypotension, immu-nosuppression and schedule-controlled behavior (Compton e