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.
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/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 -
