Chronic Δ ⁹-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 Δ ⁹-tetrahydrocannabinol (Δ ⁹-THC), and high efficacy agonists CP 55940 and WIN 55212-2, was determined before and after chronic Δ 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 Δ ⁹- THC (0.1 mg·kg ^-1, i.v.). KEY RESULTS Δ ⁹-THC decreased responding for both food presentation and stimulus-shock termination; these effects were antagonized by the CB ₁ antagonist rimonabant. Chronic Δ ⁹-THC (1 mg·kg ^-1 per 12 h, s.c.) resulted in tolerance to the rate-decreasing effects of Δ ⁹-THC and cross-tolerance to CP 55940 and WIN 55212-2; however, cross-tolerance was less than tolerance. Chronic Δ ⁹-THC increased sensitivity to rimonabant without changing sensitivity to the non-cannabinoids midazolam and ketamine. In monkeys discriminating Δ ⁹-THC (0.1 mg·kg ^-1, i.v.), both CP 55940 and WIN 55212-2 produced high levels of drug-lever responding. Chronic Δ ⁹-THC (1 mg·kg ^-1 per day, s.c.) decreased sensitivity to Δ ⁹-THC without producing cross-tolerance to CP 55940 or WIN 55212-2. CONCLUSIONS AND IMPLICATIONS In Δ 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.