Article date: March 2011
By: Lance R. McMahon in Volume 162, Issue 5, pages 1060-1073
BACKGROUND AND PURPOSE The extent to which behavioural effects vary as a function of CB1 receptor agonist efficacy is not clear. These studies tested the hypothesis that cannabinoid tolerance and cross‐tolerance depend upon the CB1 agonist efficacy of drugs to which tolerance/cross‐tolerance develops.
EXPERIMENTAL APPROACH Sensitivity to cannabinoids, including the cannabinoid antagonist rimonabant, low efficacy agonist Δ9‐tetrahydrocannabinol (Δ9‐THC), and high efficacy agonists CP 55940 and WIN 55212‐2, was determined before and after chronic Δ9‐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 Δ9‐THC (0.1 mg·kg−1, i.v.).
KEY RESULTS Δ9‐THC decreased responding for both food presentation and stimulus‐shock termination; these effects were antagonized by the CB1 antagonist rimonabant. Chronic Δ9‐THC (1 mg·kg−1 per 12 h, s.c.) resulted in tolerance to the rate‐decreasing effects of Δ9‐THC and cross‐tolerance to CP 55940 and WIN 55212‐2; however, cross‐tolerance was less than tolerance. Chronic Δ9‐THC increased sensitivity to rimonabant without changing sensitivity to the non‐cannabinoids midazolam and ketamine. In monkeys discriminating Δ9‐THC (0.1 mg·kg−1, i.v.), both CP 55940 and WIN 55212‐2 produced high levels of drug‐lever responding. Chronic Δ9‐THC (1 mg·kg−1 per day, s.c.) decreased sensitivity to Δ9‐THC without producing cross‐tolerance to CP 55940 or WIN 55212‐2.
CONCLUSIONS AND IMPLICATIONS In Δ9‐THC‐treated monkeys, the magnitude of tolerance and cross‐tolerance to other CB1 receptor agonists varied inversely with agonist efficacy, suggesting that CB1 agonist efficacy is an important determinant of behavioural effects.
DOI: 10.1111/j.1476-5381.2010.01116.x
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