Related Experiment Video
Updated: Jun 5, 2026
Administration of Δ9-Tetrahydrocannabinol (THC) in Adolescent and Adult Mice
Published on: August 1, 2025
Tolerance and cross-tolerance to cannabinoids in mice: schedule-controlled responding and hypothermia
Harinder Singh1, David R Schulze, Lance R McMahon
1Department of Pharmacology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Rationale:
Cannabinoid CB(1) receptor agonists vary in efficacy in vitro; however, relationships between efficacy and behavioral effects are unclear.
Objective:
This study examined the relationship between apparent CB(1) 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 CB(1) 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:
CB(1) receptors mediate the operant rate-decreasing 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.
Insights
Cannabinoid CB(1) agonist efficacy influences in vivo effects, impacting tolerance and cross-tolerance. This study clarifies how different efficacies of cannabinoids like Δ(9)-THC affect behavioral responses and body temperature in mice.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Cannabinoid CB(1) receptor agonists exhibit variable in vitro efficacy.
- The relationship between CB(1) agonist efficacy and in vivo behavioral outcomes remains poorly understood.
Purpose of the Study:
- To investigate the correlation between the apparent efficacy of CB(1) receptor agonists and their in vivo effects.
- To determine how varying agonist efficacies influence behavioral responses and physiological changes in mice.
Main Methods:
- Male C57BL/6J mice were trained to respond for food under a fixed ratio 30 schedule.
- Rectal temperature was measured to assess physiological effects.
- Sensitivity to cannabinoid agonists (CP 55940 > anandamide > Δ(9)-tetrahydrocannabinol [Δ(9)-THC]) and midazolam was assessed before, during, and after daily Δ(9)-THC treatment (32 mg/kg/day).
- Rimonabant was used to confirm CB(1) receptor mediation of effects on response rate.
Main Results:
- Δ(9)-THC, CP 55940, anandamide, and midazolam reduced response rates at lower doses than those causing hypothermia.
- Rimonabant antagonized the rate-decreasing effects of Δ(9)-THC and CP 55940, but not anandamide, indicating CB(1) mediation.
- Chronic Δ(9)-THC treatment induced tolerance to both rate-decreasing and hypothermic effects.
- Cross-tolerance was observed for hypothermic effects between Δ(9)-THC and CP 55940, but not for rate-decreasing effects.
- Sensitivity to anandamide and midazolam was not altered by Δ(9)-THC treatment.
Conclusions:
- CB(1) receptors mediate the operant rate-decreasing effects of Δ(9)-THC and CP 55940, but not anandamide, in mice.
- CB(1) agonist efficacy is a critical factor determining in vivo effects, particularly the development of tolerance and cross-tolerance.
- The magnitude of tolerance and cross-tolerance depends on agonist efficacy, both across different cannabinoids and for different effects of the same cannabinoid.
