Chronic Δ9-tetrahydrocannabinol treatment in rhesus monkeys: differential tolerance and cross-tolerance among cannabinoids

BACKGROUND AND PURPOSE The extent to which behavioural effects vary as a function of CB(1) receptor agonist efficacy is not clear. These studies tested the hypothesis that cannabinoid tolerance and cross-tolerance depend upon the CB(1) agonist efficacy of drugs to which tolerance/cross-tolerance develops. EXPERIMENTAL APPROACH Sensitivity to cannabinoids, including the cannabinoid antagonist rimonabant, low efficacy agonist Delta 9-tetrahydrocannabinol (Delta 9-THC), and high efficacy agonists CP 55940 and WIN 55212-2, was determined before and after chronic Delta 9-THC treatment in rhesus monkeys. Two measures of behavioural effect were assessed: effects of drugs to decrease fixed ratio responding for food presentation and stimulus-shock termination and discriminative stimulus effects in monkeys discriminating Delta 9-THC (0.1 mg center dot kg-1, i.v.). KEY RESULTS Delta 9-THC decreased responding for both food presentation and stimulus-shock termination; these effects were antagonized by the CB(1) antagonist rimonabant. Chronic Delta 9-THC (1 mg center dot kg-1 per 12 h, s.c.) resulted in tolerance to the rate-decreasing effects of Delta 9-THC and cross-tolerance to CP 55940 and WIN 55212-2; however, cross-tolerance was less than tolerance. Chronic Delta 9-THC increased sensitivity to rimonabant without changing sensitivity to the non-cannabinoids midazolam and ketamine. In monkeys discriminating Delta 9-THC (0.1 mg center dot kg-1, i.v.), both CP 55940 and WIN 55212-2 produced high levels of drug-lever responding. Chronic Delta 9-THC (1 mg center dot kg-1 per day, s.c.) decreased sensitivity to Delta 9-THC without producing cross-tolerance to CP 55940 or WIN 55212-2. CONCLUSIONS AND IMPLICATIONS In Delta 9-THC-treated monkeys, the magnitude of tolerance and cross-tolerance to other CB(1) receptor agonists varied inversely with agonist efficacy, suggesting that CB(1) agonist efficacy is an important determinant of behavioural effects.