Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Delta9-tetrahydrocannabinol.
BACKGROUND
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.
McMahon
Lance R
LR
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
D000818:Animals; D048588:Benzoxazines; D002186:Cannabinoids / Q000819:agonists / Q000037:antagonists & inhibitors; D003216:Conditioning, Operant / Q000187:drug effects; D003511:Cyclohexanols / Q000008:administration & dosage / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006213:Hallucinogens / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077285:Rimonabant; D013997:Time Factors
D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D006213:Hallucinogens; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D007649:Ketamine; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D008874:Midazolam; D000077285:Rimonabant