Tolerance and cross-tolerance to cannabinoids in mice: schedule-controlled responding and hypothermia

作者：Singh Harinder; Schulze David R; McMahon Lance R^*

来源：Psychopharmacology, 2011, 215(4): 665-675.

DOI：10.1007/s00213-010-2162-7

• Agonist efficacy
• Cannabinoid
• CB1
• Cross-tolerance
• Delta-9-tetrahydrocannabinol
• Hypothermia
• Mouse
• Schedule-controlled behavior
• Tolerance

Cannabinoid CB(1) receptor agonists vary in efficacy in vitro; however, relationships between efficacy and behavioral effects are unclear.
This study examined the relationship between apparent CB(1) agonist efficacy and in vivo effects.
Male C57BL/6J mice responded for food under a fixed ratio 30 schedule; rectal temperature was measured. Sensitivity of the mice to cannabinoid agonists (rank order efficacy in vitro reported to be CP 55940 > anandamide > Delta(9)-tetrahydrocannabinol; Delta(9)-THC) and a non-cannabinoid (the benzodiazepine midazolam) was determined before, during, and after discontinuation of daily Delta(9)-THC treatment (32 mg/kg/day, i.p.). Rimonabant was combined with cannabinoids to examine whether CB(1) receptors mediated effects on response rate.
Delta(9)-THC, CP 55940, anandamide, and midazolam decreased responding at doses smaller than those producing hypothermia. Rimonabant antagonized the rate-decreasing effects of Delta(9)-THC and CP 55940, but not those of anandamide. Delta(9)-THC treatment produced tolerance for both rate-decreasing and hypothermic effects. Delta(9)-THC treatment did not change sensitivity to the rate-decreasing effects of CP 55940, but produced cross-tolerance to CP 55940 for hypothermic effects. Delta(9)-THC treatment did not modify sensitivity to anandamide and midazolam.
CB(1) receptors mediate the operant rate-decreasing effects of Delta(9)-THC and CP 55940, but not anandamide, in mice. CB(1) agonist efficacy is an important determinant of in vivo effects, especially with regard to the magnitude of tolerance and cross-tolerance resulting from daily Delta(9)-THC treatment. This applies not only to different cannabinoids when measuring the same effect but also to the same cannabinoid when measuring different effects.

• 出版日期2011-6