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

Lance R. McMahon

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 (ED 50=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 (ED 50=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.

Original languageEnglish (US)
Pages (from-to)306-314
Number of pages9
JournalPsychopharmacology
Volume188
Issue number3
DOIs
StatePublished - Oct 2006

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rimonabant
Cannabinoid Receptor Antagonists
Dronabinol
Macaca mulatta
Cannabinoids
Midazolam
Ketamine

Keywords

  • Δ-tetrahydrocannabinol
  • Antagonist
  • Cannabinoid
  • Cannabis
  • Drug discrimination
  • Rhesus monkey
  • Rimonabant
  • SR 141716A

ASJC Scopus subject areas

  • Pharmacology

Cite this

Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9- tetrahydrocannabinol. / McMahon, Lance R.

In: Psychopharmacology, Vol. 188, No. 3, 10.2006, p. 306-314.

Research output: Contribution to journalArticle

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title = "Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9- tetrahydrocannabinol",
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 (ED 50=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 (ED 50=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.",
keywords = "Δ-tetrahydrocannabinol, Antagonist, Cannabinoid, Cannabis, Drug discrimination, Rhesus monkey, Rimonabant, SR 141716A",
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T1 - Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9- tetrahydrocannabinol

AU - McMahon, Lance R.

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N2 - 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 (ED 50=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 (ED 50=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.

AB - 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 (ED 50=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 (ED 50=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.

KW - Δ-tetrahydrocannabinol

KW - Antagonist

KW - Cannabinoid

KW - Cannabis

KW - Drug discrimination

KW - Rhesus monkey

KW - Rimonabant

KW - SR 141716A

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