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

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Abstract

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 > Δ9-tetrahydrocannabinol; Δ9-THC) and a non-cannabinoid (the benzodiazepine midazolam) was determined before, during, and after discontinuation of daily Δ9-THC treatment (32 mg/kg/day, i.p.). Rimonabant was combined with cannabinoids to examine whether CB1 receptors mediated effects on response rate.

Results

Δ9-THC, CP 55940, anandamide, and midazolam decreased responding at doses smaller than those producing hypothermia. Rimonabant antagonized the rate-decreasing effects of Δ9-THC and CP 55940, but not those of anandamide. Δ9-THC treatment produced tolerance for both rate-decreasing and hypothermic effects. Δ9-THC treatment did not change sensitivity to the rate-decreasing effects of CP 55940, but produced cross-tolerance to CP 55940 for hypothermic effects. Δ9-THC treatment did not modify sensitivity to anandamide and midazolam.

Conclusions

CB1 receptors mediate the operant rate-decreasing effects of Δ9-THC and CP 55940, but not anandamide, in mice. CB1 agonist efficacy is an important determinant of in vivo effects, especially with regard to the magnitude of tolerance and cross-tolerance resulting from daily Δ9-THC treatment. This applies not only to different cannabinoids when measuring the same effect but also to the same cannabinoid when measuring different effects.

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Acknowledgments

Supported by U.S. Public Health Service Grants DA19222 and DA26781.

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Authors and Affiliations

  1. Department of Pharmacology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Harinder Singh, David R. Schulze & Lance R. McMahon

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  1. Harinder Singh
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  2. David R. Schulze
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  3. Lance R. McMahon
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Correspondence to Lance R. McMahon.

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Singh, H., Schulze, D.R. & McMahon, L.R. Tolerance and cross-tolerance to cannabinoids in mice: schedule-controlled responding and hypothermia. Psychopharmacology 215, 665–675 (2011). https://doi.org/10.1007/s00213-010-2162-7

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  • DOI: https://doi.org/10.1007/s00213-010-2162-7

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