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Chronic Δ⁹-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 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.

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  • Authors+Show Affiliations

    Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. mcmahonl@uthscsa.edu

    Source

    British journal of pharmacology 162:5 2011 Mar pg 1060-73

    MeSH

    Animals
    Behavior, Animal
    Benzoxazines
    Cannabinoids
    Cyclohexanols
    Discrimination Learning
    Dose-Response Relationship, Drug
    Dronabinol
    Drug Tolerance
    Female
    Macaca mulatta
    Male
    Morpholines
    Naphthalenes
    Piperidines
    Pyrazoles
    Receptor, Cannabinoid, CB1
    Rimonabant

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    21091643

    Citation

    McMahon, Lance R.. "Chronic Δ⁹-tetrahydrocannabinol Treatment in Rhesus Monkeys: Differential Tolerance and Cross-tolerance Among Cannabinoids." British Journal of Pharmacology, vol. 162, no. 5, 2011, pp. 1060-73.
    McMahon LR. Chronic Δ⁹-tetrahydrocannabinol treatment in rhesus monkeys: differential tolerance and cross-tolerance among cannabinoids. Br J Pharmacol. 2011;162(5):1060-73.
    McMahon, L. R. (2011). Chronic Δ⁹-tetrahydrocannabinol treatment in rhesus monkeys: differential tolerance and cross-tolerance among cannabinoids. British Journal of Pharmacology, 162(5), pp. 1060-73. doi:10.1111/j.1476-5381.2010.01116.x.
    McMahon LR. Chronic Δ⁹-tetrahydrocannabinol Treatment in Rhesus Monkeys: Differential Tolerance and Cross-tolerance Among Cannabinoids. Br J Pharmacol. 2011;162(5):1060-73. PubMed PMID: 21091643.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Chronic Δ⁹-tetrahydrocannabinol treatment in rhesus monkeys: differential tolerance and cross-tolerance among cannabinoids. A1 - McMahon,Lance R, PY - 2010/11/25/entrez PY - 2010/11/26/pubmed PY - 2011/5/7/medline SP - 1060 EP - 73 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 162 IS - 5 N2 - 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/21091643/abstract/Chronic_Δ⁹_tetrahydrocannabinol_treatment_in_rhesus_monkeys:_differential_tolerance_and_cross_tolerance_among_cannabinoids_ L2 - https://doi.org/10.1111/j.1476-5381.2010.01116.x DB - PRIME DP - Unbound Medicine ER -