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Cannabinoid agonists differentially substitute for the discriminative stimulus effects of Δ9-tetrahydrocannabinol in C57BL/6J mice

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Abstract

Rationale

A variety of behavioral procedures have been developed to assess cannabinoid activity in mice; however, the feasibility of establishing Δ9-THC as a discriminative stimulus in mice has not been documented.

Objective

One goal was to establish Δ9-THC as a discriminative stimulus in mice; after having done so, another goal was to examine the in vivo mechanism of action of Δ9-THC with other cannabinoids and noncannabinoids.

Materials and methods

C57BL/6J mice (n = 8) were trained to discriminate Δ9-THC (10 mg/kg i.p.) from vehicle while responding under a fixed ratio 30 schedule of food presentation.

Results

Mice satisfied the discrimination criteria in 18–98 (median = 67) sessions and the discriminative stimulus effects of Δ9-THC were dose-dependent (ED50 = 2.6 mg/kg). CP 55940 and WIN 55212-2 dose-dependently increased Δ9-THC-appropriate responding to 100% (ED50 = 0.032 and 0.45 mg/kg, respectively), whereas methanandamide and a variety of noncannabinoids (cocaine, ethanol, and ketamine) produced a maximum of 34% Δ9-THC-appropriate responding. The cannabinoid CB1 antagonist SR 141716A (rimonabant) surmountably antagonized the discriminative effects of Δ9-THC, CP 55940, and WIN 55212-2; methanandamide did not significantly modify the Δ9-THC discriminative stimulus.

Conclusions

The discriminative stimulus effects of Δ9-THC, CP 55940, and WIN 55212-2 are mediated by the same (i.e., CB1) receptors, whereas the effects of methanandamide or a metabolite of methanandamide are mediated at least in part by non-CB1 receptors. The discriminative stimulus effects of Δ9-THC in mice could be used to evaluate mechanisms of cannabinoid activity with approaches (e.g., inducible knockouts) currently unavailable in nonmurine species.

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Acknowledgments

The authors thank G. Martinez for providing technical assistance.

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Authors and Affiliations

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

    Lance R. McMahon & R. J. Lamb

  2. Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Brett C. Ginsburg & R. J. Lamb

Authors
  1. Lance R. McMahon
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  2. Brett C. Ginsburg
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  3. R. J. Lamb
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Corresponding author

Correspondence to Lance R. McMahon.

Additional information

Supported by U.S. Public Health Service Grants DA15468, DA19222, and AA012337.

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McMahon, L.R., Ginsburg, B.C. & Lamb, R.J. Cannabinoid agonists differentially substitute for the discriminative stimulus effects of Δ9-tetrahydrocannabinol in C57BL/6J mice. Psychopharmacology 198, 487–495 (2008). https://doi.org/10.1007/s00213-007-0900-2

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  • DOI: https://doi.org/10.1007/s00213-007-0900-2

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