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Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9-tetrahydrocannabinol

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Abstract

Rationale

Drug discrimination can be used to examine tolerance and dependence in agonist-treated animals by establishing an appropriate antagonist as a discriminative stimulus.

Objective

Establish intravenous SR 141716A as a discriminative stimulus in four rhesus monkeys pretreated with a relatively small dose of Δ9-tetrahydrocannabinol (Δ9-THC).

Methods

Rhesus monkeys received i.v. Δ9-THC (0.32 mg/kg) and discriminated i.v. SR 141716A (1 mg/kg) from vehicle while responding under a fixed ratio (FR) 5 schedule of stimulus-shock termination.

Results

The discriminative stimulus effects of SR 141716A were dose-dependent (ED50=0.33 mg/kg) and were mimicked by the CB1 antagonist AM 251 (ED50=0.98 mg/kg), but not by a benzodiazepine (midazolam) or an N-methyl-D-aspartate antagonist (ketamine). An additional dose (0.32 mg/kg in addition to 0.32 mg/kg administered before the session) of Δ9-THC shifted the SR 141716A dose–effect curve 3-fold rightward. Omitting Δ9-THC before test sessions resulted in responding on the SR 141716A lever that was attenuated by subsequent administration of Δ9-THC (ED50=0.13 mg/kg), CP 55940 (ED50=0.013 mg/kg), and WIN 55212-2 (ED50=0.35 mg/kg); midazolam and ketamine did not attenuate responding on the SR 141716A lever. SR 141716A (1 mg/kg) shifted the Δ9-THC and CP 55940 dose–effect curves 3.4-fold rightward; the WIN 55212-2 dose–effect curve was not significantly modified by a dose of 1 mg/kg of SR 141716A.

Conclusions

SR 141716A can be established as a discriminative stimulus in animals pretreated with Δ9-THC, and this assay is selective for cannabinoid activity. Differential antagonism of cannabinoids by SR 141716A might indicate that the mechanism of action of WIN 55212-2 is not identical to other cannabinoids. This study demonstrates that, under the appropriate conditions, drug discrimination has utility for examining cannabinoid dependence and withdrawal.

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Acknowledgments

Supported by US Public Health Service Grants DA15468 and DA19222. The author thanks C. Cruz, M. Hernandez, and D. Logan 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

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  1. Lance R. McMahon
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Correspondence to Lance R. McMahon.

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McMahon, L.R. Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9-tetrahydrocannabinol. Psychopharmacology 188, 306–314 (2006). https://doi.org/10.1007/s00213-006-0500-6

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  • DOI: https://doi.org/10.1007/s00213-006-0500-6

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