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Chronic Δ⁹-tetrahydrocannabinol treatment in rhesus monkeys: differential tolerance and cross-tolerance among cannabinoids.
Br J Pharmacol 2011; 162(5):1060-73BJ

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.

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

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_Δ�%B L2 - https://doi.org/10.1111/j.1476-5381.2010.01116.x DB - PRIME DP - Unbound Medicine ER -