Chronic Δ 9-tetrahydrocannabinol treatment in rhesus monkeys: Differential tolerance and cross-tolerance among cannabinoids

Lance R. McMahon

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1060-1073
Number of pages14
JournalBritish Journal of Pharmacology
Issue number5
StatePublished - Mar 2011


  • cannabinoid
  • cross-tolerance
  • drug discrimination
  • efficacy
  • fixed ratio responding
  • rhesus monkey
  • tolerance

ASJC Scopus subject areas

  • Pharmacology


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