Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Δ⁹-tetrahydrocannabinol

Rationale: Anandamide and Δ⁹-tetrahydrocannabinol (Δ⁹-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 Δ⁹-THC, anandamide, and two structural analogs of anandamide in rhesus monkeys. Materials and methods: Monkeys discriminated Δ⁹-THC (0.1 mg/kg i.v.) from vehicle. Δ⁹-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: Δ⁹-THC, ACPA, methanandamide, and anandamide produced greater than 96% of responses on the Δ⁹-THC lever. The ED₅₀ values were 0.024 mg/kg for Δ⁹-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 Δ⁹-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 Δ⁹-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.