Antagonism of discriminative stimulus effects of delta(9)-THC and (R)-methanandamide in rats.
BACKGROUND
In previous drug discrimination studies we observed surmountable antagonism by Delta(9)-tetrahydrocannabinol (THC) in the presence of constant doses of SR-141716 [N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] (0.3 and 1 mg/kg), but there was only marginal evidence for surmountable antagonism with combinations of SR-141716 and (R)-methanandamide, a chiral analog of the endocannabioid anandamide.


OBJECTIVE
Here we examine antagonism where the cannabinoid CB1 receptor agonist [Delta(9)-THC and (R)-methanandamide] dose is held constant (i.e., the training dose) and the antagonist {i.e., SR-141716 and AM-251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; 2 ml/kg]} dose varied. We also tested the cannabinoid CB2 receptor antagonist SR-144528 {N-[(1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide}.


METHODS
Different groups of rats were trained to discriminate between vehicle and three different doses of Delta(9)-THC (1.8, 3, and 5.6 mg/kg, presumably reflecting different efficacy demands) as well as 10 mg/kg (R)-methanandamide. Dose-generalization tests involved different doses of the cannabinoid CB1 receptor agonists. Antagonist tests varied the dose of the antagonist (range: 0.1 and 3 mg/kg for SR-141716 and AM-251, and 1 to 10 mg/kg for SR-144528).


RESULTS
SR-141716 and AM-251 doses dependently blocked the agonist-induced discriminative stimulus effects. SR-141716 tended to be slightly more potent than AM-251. The effective dose 50 (ED(50)) of SR-141716 was higher in the 5.6 mg/kg Delta(9)-THC-trained group relative to the two other Delta(9)-THC-trained groups. The cannabinoid CB2 receptor antagonist SR-144528 combined with the training dose of 1.8 mg/kg Delta(9)-THC, as well as when combined with the training dose of 10 mg/kg (R)-methanandamide, did not markedly change drug-appropriate (agonist) responses.


CONCLUSIONS
Data support that the discriminative stimulus effects of (R)-methanandamide and its overlap with the Delta(9)-THC cue are, indeed, CB1 receptor mediated events as revealed in antagonism tests with the selective central CB1 receptor antagonists SR-141716 and AM-251. The activation of cannabinoid CB2 receptors appears to be insignificant for these discriminations.
Järbe
Torbjörn U C
TU
Department of Psychology, Temple University, 265-67 Weiss Hall, 1701 North 13th Street, Philadelphia, PA 19122, USA. tjarbe@excite.com
Liu
Quian
Q
Makriyannis
Alexandros
A
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001892:Camphanes / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004336:Drug Antagonism; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013237:Stereoisomerism
D001095:Arachidonic Acids; D001892:Camphanes; C469526:Cnr2 protein, rat; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; C088155:methanandamide; C103505:AM 251; D013759:Dronabinol; D000077285:Rimonabant