Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Delta(9)-tetrahydrocannabinol

作者：McMahon Lance R^*

来源：Psychopharmacology, 2009, 203(2): 219-228.

DOI：10.1007/s00213-008-1230-8

• Anandamide
• Arachidonylcyclopropylamide
• Cannabinoid
• Delta(9)-tetrahydrocannabinol
• Drug discrimination
• Methanandamide
• Rhesus monkey
• Rimonabant
• Schild analysis
• SR 141716A

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.
Drug discrimination was used to compare the mechanism of action of Delta(9)-THC, anandamide, and two structural analogs of anandamide in rhesus monkeys.
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.
Delta(9)-THC, ACPA, methanandamide, and anandamide produced greater than 96% of responses on the Delta(9)-THC lever. The ED50 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.
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.

• 出版日期2009-4