Lance R McMahon1. 1. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA. mcmahonl@uthscsa.edu
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 Delta9-tetrahydrocannabinol (Delta9-THC). METHODS: Rhesus monkeys received i.v. Delta9-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 Delta9-THC shifted the SR 141716A dose-effect curve 3-fold rightward. Omitting Delta9-THC before test sessions resulted in responding on the SR 141716A lever that was attenuated by subsequent administration of Delta9-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 Delta9-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 Delta9-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.
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 Delta9-tetrahydrocannabinol (Delta9-THC). METHODS:Rhesus monkeys received i.v. Delta9-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 Delta9-THC shifted the SR 141716A dose-effect curve 3-fold rightward. Omitting Delta9-THC before test sessions resulted in responding on the SR 141716A lever that was attenuated by subsequent administration of Delta9-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 Delta9-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 Delta9-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.
Authors: Caroline E Bass; Graeme Griffin; Mark Grier; Anu Mahadevan; Raj K Razdan; Billy R Martin Journal: Pharmacol Biochem Behav Date: 2002-12 Impact factor: 3.533
Authors: Brian D Kangas; Marcus S Delatte; V Kiran Vemuri; Ganesh A Thakur; Spyridon P Nikas; Kumara V Subramanian; Vidyanand G Shukla; Alexandros Makriyannis; Jack Bergman Journal: J Pharmacol Exp Ther Date: 2013-01-03 Impact factor: 4.030