CANNABINOID-PRECIPITATED WITHDRAWAL - A TIME-COURSE STUDY OF THE BEHAVIORAL-ASPECT AND ITS CORRELATION WITH CANNABINOID RECEPTORS AND G-PROTEIN EXPRESSION

To characterize the time course of the behavioral and biochemical aspe cts of the cannabinoid withdrawal syndrome, we injected the cannabinoi d antagonist SR141716A (5 mg/kg i.p.) in rats made tolerant to CP-55,9 40 (0.4 mg/kg i.p., twice daily for 6.5 days), 1, 24 and 96 h after th e last CP-55,940 injection. Because the CB1 receptor and G protein alp ha subunit are involved in cannabinoid tolerance, we observed their ch anges throughout the brain during the withdrawal syndrome by use of in situ hybridization. In vehicle-pretreated rats SR141716A per se induc ed abnormal behavior significantly different from the vehicle group: w et dog shakes, forepaw fluttering and scratching. These signs remained significantly elevated even after the second and third antagonist dos es. SR141716A significantly modified the mRNA levels of G alpha s and G alpha i subunits in some brain areas without affecting CB1 receptor and G alpha o expression. These findings led us to conclude that SR141 716A may have intrinsic activity. Concerning cannabinoid withdrawal, t he first SR141716A injection in tolerant rats resulted in behavioral s igns different from those observed with the antagonist alone; this mod erate withdrawal syndrome was characterized by turning, chewing and di gging. Additional SR141716A doses 24 and 96 h later did not induce a s ignificant abstinence syndrome. In situ hybridization after the first SR141716A injection showed that CB1 receptor and G protein alpha subun its, whose levels were low in tolerance, recovered their basal level o f expression. Thus, the general desensitization of the cannabinoid rec eptor and of the transduction system in tolerance are recovered in abs tinent rats and might be part of the molecular mechanisms underlying c annabinoid dependence.