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Vol. 285, Issue 3, 1150-1156, June 1998

CB1 Receptor Antagonist Precipitates Withdrawal in Mice Exposed to 
9-Tetrahydrocannabinol1

Stacie A. Cook, John A. Lowe and Billy R. Martin

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia and Pfizer Central Research, Pfizer Inc., Groton, Connecticut

Although tolerance to cannabinoids has been well established, the question of  cannabinoid dependence had been very controversial until the discovery of a cannabinoid antagonist, SR141716A. The objective of this study was to develop and characterize a mouse model of precipitated withdrawal indicative of cannabinoid dependence. Using a dosing regimen known to produce pharmacological and behavioral tolerance, mice were treated with 9-tetrahydrocannabinol (9-THC) twice a day for 1 wk. SR141716A administration after the last 9-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 decrease in normal behavior such as grooming and scratching. Of the three 9-THC regimens tested, daily 9-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 challenge with SR141716A. Precipitated withdrawal was apparent after 2, 3, 7 and 14 days of treatment based on an increase in paw tremors in 9-THC-treated mice as compared with vehicle-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.

THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

Copyright 1998 by the American Society for Pharmacology and Experimental 
Therapeutics.

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