(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, Richard J Lamb, S. Lin, A. Makriyannis

Research output: Contribution to journalArticle

74 Citations (Scopus)

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
Externally publishedYes

Fingerprint

rimonabant
Cannabinoid Receptor Antagonists
Dronabinol
Ligands
methanandamide
anandamide

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

(R)-methanandamide and Δ9-THC as discriminative stimuli in rats : Tests with the cannabinoid antagonist SR-141716 and the endogenous ligand anandamide. / Järbe, T. U C; Lamb, Richard J; Lin, S.; Makriyannis, A.

In: Psychopharmacology, Vol. 156, No. 4, 2001, p. 369-380.

Research output: Contribution to journalArticle

@article{cf7fb264c7104ad287e405023dfafb7d,
title = "(R)-methanandamide and Δ9-THC as discriminative stimuli in rats: Tests with the cannabinoid antagonist SR-141716 and the endogenous ligand anandamide",
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.",
keywords = "Δ-THC, (R)-Methanandamide, Anandamide, Antagonism, Cannabinoid, Discriminative stimulus, Drug discrimination, Rat, SR-141716",
author = "J{\"a}rbe, {T. U C} and Lamb, {Richard J} and S. Lin and A. Makriyannis",
year = "2001",
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pages = "369--380",
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TY - JOUR

T1 - (R)-methanandamide and Δ9-THC as discriminative stimuli in rats

T2 - Tests with the cannabinoid antagonist SR-141716 and the endogenous ligand anandamide

AU - Järbe, T. U C

AU - Lamb, Richard J

AU - Lin, S.

AU - Makriyannis, A.

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

KW - Δ-THC

KW - (R)-Methanandamide

KW - Anandamide

KW - Antagonism

KW - Cannabinoid

KW - Discriminative stimulus

KW - Drug discrimination

KW - Rat

KW - SR-141716

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U2 - 10.1007/s002130100730

DO - 10.1007/s002130100730

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VL - 156

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JO - Psychopharmacology

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SN - 0033-3158

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