Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Delta9-tetrahydrocannabinol.
BACKGROUND
Anandamide and Delta(9)-tetrahydrocannabinol (Delta(9)-THC) sometimes produce different discriminative stimulus effects and, therefore, appear to differ in their mechanism of action. In order to understand the widespread use of cannabis and the therapeutic potential of cannabinoids, mechanisms responsible for behavioral effects need to be identified.


OBJECTIVE
Drug discrimination was used to compare the mechanism of action of Delta(9)-THC, anandamide, and two structural analogs of anandamide in rhesus monkeys.


METHODS
Monkeys discriminated Delta(9)-THC (0.1 mg/kg i.v.) from vehicle. Delta(9)-THC, anandamide, methanandamide, and arachidonylcyclopropylamide (ACPA) were administered i.v. alone and in combination with at least one dose of rimonabant. Schild analysis and single-dose apparent affinity estimates were used to estimate the potency of rimonabant as an antagonist of each cannabinoid; these values were compared to examine whether the same receptors mediated discriminative stimulus effects.


RESULTS
Delta(9)-THC, ACPA, methanandamide, and anandamide produced greater than 96% of responses on the Delta(9)-THC lever. The ED(50) values were 0.024 mg/kg for Delta(9)-THC, 0.14 mg/kg for ACPA, 0.28 mg/kg for methanandamide, and 1.7 mg/kg for anandamide. The duration of action of Delta(9)-THC was 4-6 h and longer than the duration of action ACPA, methanandamide, and anandamide (i.e., each less than 50 min). Rimonabant surmountably antagonized the discriminative stimulus effects of each agonist, and the apparent affinity estimates (pA (2) and pK (B) values) were 6.24-6.83.


CONCLUSIONS
Rimonabant can produce surmountable antagonism of the behavioral effects of not only Delta(9)-THC but also anandamide, methanandamide, and ACPA, and the interactions appear simple, competitive, and reversible. These cannabinoid agonists act at the same receptors to produce discriminative stimulus effects.
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; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D063388:Endocannabinoids; D005260:Female; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000077285:Rimonabant; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D013759:Dronabinol; D000077285:Rimonabant; C078814:anandamide