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Chronic Δ 9 ‐tetrahydrocannabinol treatment in rhesus monkeys: differential tolerance and cross‐tolerance among cannabinoids
Author(s) -
McMahon Lance R.
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01116.x
Subject(s) - rimonabant , cross tolerance , dronabinol , cannabinoid , drug tolerance , agonist , pharmacology , delta 9 tetrahydrocannabinol , cannabinoid receptor , tetrahydrocannabinol , antagonist , inverse agonist , medicine , morphine , receptor
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.