Cannabinoid agonists differentially substitute for the discriminative stimulus effects of Delta(9)-tetrahydrocannabinol in C57BL/6J mice.
BACKGROUND
A variety of behavioral procedures have been developed to assess cannabinoid activity in mice; however, the feasibility of establishing Delta(9)-THC as a discriminative stimulus in mice has not been documented.


OBJECTIVE
One goal was to establish Delta(9)-THC as a discriminative stimulus in mice; after having done so, another goal was to examine the in vivo mechanism of action of Delta(9)-THC with other cannabinoids and noncannabinoids.


METHODS
C57BL/6J mice (n = 8) were trained to discriminate Delta(9)-THC (10 mg/kg i.p.) from vehicle while responding under a fixed ratio 30 schedule of food presentation.


RESULTS
Mice satisfied the discrimination criteria in 18-98 (median = 67) sessions and the discriminative stimulus effects of Delta(9)-THC were dose-dependent (ED(50) = 2.6 mg/kg). CP 55940 and WIN 55212-2 dose-dependently increased Delta(9)-THC-appropriate responding to 100% (ED(50) = 0.032 and 0.45 mg/kg, respectively), whereas methanandamide and a variety of noncannabinoids (cocaine, ethanol, and ketamine) produced a maximum of 34% Delta(9)-THC-appropriate responding. The cannabinoid CB(1) antagonist SR 141716A (rimonabant) surmountably antagonized the discriminative effects of Delta(9)-THC, CP 55940, and WIN 55212-2; methanandamide did not significantly modify the Delta(9)-THC discriminative stimulus.


CONCLUSIONS
The discriminative stimulus effects of Delta(9)-THC, CP 55940, and WIN 55212-2 are mediated by the same (i.e., CB(1)) receptors, whereas the effects of methanandamide or a metabolite of methanandamide are mediated at least in part by non-CB(1) receptors. The discriminative stimulus effects of Delta(9)-THC in mice could be used to evaluate mechanisms of cannabinoid activity with approaches (e.g., inducible knockouts) currently unavailable in nonmurine species.
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.
Ginsburg
Brett C
BC
Lamb
R J
RJ
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D002186:Cannabinoids / Q000819:agonists*; D003511:Cyclohexanols / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004347:Drug Interactions; D006213:Hallucinogens / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D012055:Reinforcement Schedule; D000077285:Rimonabant
D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D006213:Hallucinogens; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C088155:methanandamide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant