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

Rationale Cannabinoid CB1 receptor agonists vary in efficacy in vitro; however, relationships between efficacy and behavioral effects are unclear. Objective This study examined the relationship between apparent CB1 agonist efficacy and in vivo effects. Methods 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>Δ ⁹-tetrahydrocannabinol; Δ ⁹-THC) and a non-cannabinoid (the benzodiazepine midazolam) was determined before, during, and after discontinuation of daily Δ ⁹-THC treatment (32 mg/kg/day, i.p.). Rimonabant was combined with cannabinoids to examine whether CB1 receptors mediated effects on response rate. Results Δ ⁹-THC, CP 55940, anandamide, and midazolam decreased responding at doses smaller than those producing hypothermia. Rimonabant antagonized the rate-decreasing effects of Δ ⁹-THC and CP 55940, but not those of anandamide. Δ ⁹-THC treatment produced tolerance for both rate-decreasing and hypothermic effects. Δ 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. Δ ⁹-THC treatment did not modify sensitivity to anandamide and midazolam. Conclusions CB1 receptors mediate the operant ratedecreasing effects of Δ 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 Δ 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.