The fatty acid amide hydrolase inhibitor URB 597: interactions with anandamide in rhesus monkeys

Abstract

The fatty acid amide hydrolase inhibitor URB 597 increases brain anandamide levels, suggesting that URB 597 could enhance the behavioural effects of anandamide. The goal of the current study was to examine and characterize the in vivo pharmacology of URB 597 alone and in combination with anandamide and Δ⁹-tetrahydrocannabinol (Δ⁹ -THC) in two drug discrimination assays in rhesus monkeys. The effects of URB 597 alone and in combination with anandamide were investigated in one group of monkeys (n= 4) that discriminated Δ⁹-THC (0.1 mg·kg⁻¹ i.v.) from vehicle, and in another group (n= 5) receiving chronic Δ⁹-THC (1 mg·kg⁻¹ 12 h⁻¹ s.c.) that discriminated the cannabinoid antagonist rimonabant (1 mg·kg⁻¹ i.v.). Intravenous anandamide fully substituted for, and had infra-additive effects with, Δ⁹-THC. URB 597 (up to 3.2 mg·kg⁻¹ i.v.) did not substitute for or modify the effects of Δ⁹-THC but markedly increased the potency (32-fold) and duration of action of anandamide. The rimonabant discriminative stimulus in Δ⁹-THC-treated monkeys (i.e. Δ⁹-THC withdrawal) was attenuated by both Δ⁹-THC (at doses larger than 1 mg·kg⁻¹ per 12 h) and anandamide but not by URB 597 (3.2 mg·kg⁻¹). URB 597 did not increase the potency of anandamide to attenuate the rimonabant-discriminative stimulus. URB 597 enhanced the behavioural effects of anandamide but not other CB₁ agonists. However, URB 597 did not significantly enhance the attenuation of Δ⁹-THC withdrawal induced by anandamide. Collectively, these data suggest that endogenous anandamide in primate brain does not readily mimic the behavioural effects of exogenously administered anandamide.