Dataset Information

Chronic ??-tetrahydrocannabinol treatment in rhesus monkeys: differential tolerance and cross-tolerance among cannabinoids.

ABSTRACT:

Background and purpose

The extent to which behavioural effects vary as a function of CB? receptor agonist efficacy is not clear. These studies tested the hypothesis that cannabinoid tolerance and cross-tolerance depend upon the CB? agonist efficacy of drugs to which tolerance/cross-tolerance develops.

Experimental approach

Sensitivity to cannabinoids, including the cannabinoid antagonist rimonabant, low efficacy agonist ??-tetrahydrocannabinol (??-THC), and high efficacy agonists CP 55940 and WIN 55212-2, was determined before and after chronic ??-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 ??-THC (0.1 mg·kg?¹, i.v.).

Key results

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

Conclusions and implications

In ??-THC-treated monkeys, the magnitude of tolerance and cross-tolerance to other CB? receptor agonists varied inversely with agonist efficacy, suggesting that CB? agonist efficacy is an important determinant of behavioural effects.

SUBMITTER: McMahon LR

PROVIDER: S-EPMC3051379 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Publications

Chronic Δ⁹-tetrahydrocannabinol treatment in rhesus monkeys: differential tolerance and cross-tolerance among cannabinoids.

McMahon Lance R LR

British journal of pharmacology 20110301 5

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Sensitivity to cannabinoids, including the cannabinoid antagonist rimonabant, low efficacy agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC), and high efficacy agonists ...[more]

PMID: 21091643

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