TY - JOUR
T1 - Chronic Δ 9-tetrahydrocannabinol treatment in rhesus monkeys
T2 - Differential tolerance and cross-tolerance among cannabinoids
AU - McMahon, Lance R.
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - cannabinoid
KW - cross-tolerance
KW - drug discrimination
KW - efficacy
KW - fixed ratio responding
KW - rhesus monkey
KW - tolerance
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U2 - 10.1111/j.1476-5381.2010.01116.x
DO - 10.1111/j.1476-5381.2010.01116.x
M3 - Article
C2 - 21091643
AN - SCOPUS:79551486841
VL - 162
SP - 1060
EP - 1073
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 5
ER -