Abstract
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 Δ9-tetrahydrocannabinol (Δ9-THC) twice a day for 1 wk. SR141716A administration after the last Δ9-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 Δ9-THC regimens tested, daily Δ9-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 Δ9-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.
Footnotes
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Send reprint requests to: Dr. Billy R. Martin, Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Box 980613, MCV Station Richmond, VA 23298-0613.
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↵1 This work was supported by NIDA Grants DA 03672 and Training Grant DA 07027.
- Abbreviations:
- Δ9-THC
- Δ9-tetrahydrocannabinol
- SR141716A
- N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide
- C.L.
- confidence limits
- Received August 7, 1997.
- Accepted February 12, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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