(R)-methanandamide and Δ9-THC as discriminative stimuli in rats: Tests with the cannabinoid antagonist SR-141716 and the endogenous ligand anandamide

T. U.C. Järbe, R. J. Lamb, S. Lin, A. Makriyannis

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Rationale and objectives: (R)-Methanandamide (AM-356), a metabolically more stable chiral analog of the endocannabinoid ligand anandamide, was used as a representative of fatty acid ethanolamide CB1 receptor ligands to characterize the discriminative stimulus functions of anandamides. Methods: Rats discriminated between 10 mg/kg (R)-methanandamide and vehicle administered IP 15 min prior to session onset. Another group of rats was initially trained to discriminate between 3 mg/kg Δ9-THC and vehicle given IP 30 min prior to session onset; for anandamide testing, the animals were retrained with 1.8 and 5.6 mg/kg Δ9-THC. A two lever operant methodology (FR10) was used. Results: Δ9-THC was more potent than (R)-methanandamide at both 15 and 30 min post-injection, irrespective of the training drug used. Additional tests with 10 and 18 mg/kg (R)-methanandamide suggested that the effects were declining by 1 h. The cannabinoid antagonist SR 141716 (0.3 and 1 mg/kg) produced rightward shifts in the Δ9-THC dose-response curve for Δ9-THC-appropriate responding and for (R)-methanandamide-appropriate responding (surmountable antagonism). SR-141716 (0.3 and 1 mg/kg) antagonized the ability of (R)-methanandamide to occasion either Δ9-THC-appropriate responding or (R)-methanandamide-appropriate responding. This antagonism was surmountable only at a dose of 0.3 mg/kg SR-1421716 in the (R)-methanandamide-trained rats. SR-141716 did not antagonize the rate-decreasing effects of (R)-methanandamide in either the Δ9-THC or the (R)-methanandamide trained rats. Response suppression precluded testing doses higher than 30 mg/kg (R)-methanandamide. Tests with SR-141716 (1 and 10 mg/kg) alone resulted in <3% Δ9-THC-appropriate responding. With 10 mg/kg SR-141716, response rate was significantly lower as compared to the rate observed during a vehicle test. Tests with anandamide (10 and 18 mg/kg) resulted in 41% and 85% (R)-methanandamide-appropriate responding at a 3-min pre-treatment time, but in a maximum of 15% (R)-methanandamide-appropriate responding at a longer (15 min) pre-treatment time. In the Δ9-THC (1.8 and 5.6 mg/kg) trained rats, anandamide never produced more than about 20% Δ9-THC-appropriate responding. Conclusion: The results add to a growing body of evidence indicating that there are both similarities and dissimilarities between classical cannabinoids such as THC and endogenous fatty acid ethanolamides.

Original languageEnglish (US)
Pages (from-to)369-380
Number of pages12
JournalPsychopharmacology
Volume156
Issue number4
DOIs
StatePublished - 2001

Keywords

  • (R)-Methanandamide
  • Anandamide
  • Antagonism
  • Cannabinoid
  • Discriminative stimulus
  • Drug discrimination
  • Rat
  • SR-141716
  • Δ-THC

ASJC Scopus subject areas

  • Pharmacology

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