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

Lance R. McMahon, Brett C. Ginsburg, R. J. Lamb

Research output: Contribution to journalArticle

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)487-495
Number of pages9
JournalPsychopharmacology
Volume198
Issue number4
DOIs
StatePublished - Jul 1 2008

Keywords

  • Antagonist
  • Cannabinoid
  • Drug discrimination
  • Efficacy
  • Mouse
  • Rimonabant
  • SR 141716A
  • Δ-THC

ASJC Scopus subject areas

  • Pharmacology

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