Precipitated cannabinoid withdrawal is reversed by Delta(9)-tetrahydrocannabinol or clonidine

The availability of the cannabinoid antagonist, SR 141716A, to precipitate withdrawal following repeated cannabinoid administration provides a model t o investigate the mechanisms underlying cannabinoid dependence as well as p otential treatments to alleviate withdrawal symptoms. The goal of the prese nt study was to determine whether SR 141716A-precipitated withdrawal sympto ms in Delta (9)-tetrahydrocannabinol (Delta (9)-THC)-tolerant mice could be alleviated by either readministration of Delta (9)-THC or clonidine, an al pha (2)-receptor agonist. SR 141716A elicited paw tremors in Delta (9)-THC- tolerant mice, but produced a significant increase in head shakes independe ntly of repeated Delta (9)-THC treatment. Readministration of Delta (9)-THC , following SR 141716A-precipitated withdrawal, reversed paw tremors (ED50 = 9.9 mg/kg), but failed to reduce head shaking behavior. Clonidine reverse d SR 141716A-precipitated paw tremors (ED50 = 0.18 mg/kg) and blocked head shakes at all doses tested. The reversal effects did not appear to be the r esult of motor impairment because neither decreases in spontaneous locomoto r activity nor motor incoordination, as assessed in the inverted screen tes t, could account for the effects. These findings suggest that SR 141716A pr ecipitates paw tremors in mice by competing with Delta (9)-THC at the CBI r eceptor, though it also produced head shaking in nondependent animals. Fina lly, the observation that clonidine alleviated SR 141716A-precipitated paw tremors suggests its potential as a treatment for cannabinoid dependence. ( C) 2001 Elsevier Science Inc. All rights reserved.