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

Abstract

Background and purpose: 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.

Experimental approach: 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.).

Key results: 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.

Conclusions and implications: 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.

Figure 1

Effects of Δ⁹-THC and anandamide, alone (top) and in combination (bottom), in monkeys discriminating Δ⁹-THC (0.1 mg·kg⁻¹ i.v.) from vehicle. Abscissae: vehicle (V) or dose in mg·kg⁻¹ body weight. Ordinates: mean (±SEM) percentage of responding on the Δ⁹-THC lever. The composite additive line was determined from linear regression of all data from the individual dose–response curves (top panel) expressed as a function of the theoretically derived, combined total dose of Δ⁹-THC and anandamide (bottom panel, composite additive). The solid line in the bottom panel was determined from linear regression of the experimentally derived data produced by the combination of Δ⁹-THC and anandamide.

Figure 2

Effects of URB 597, alone and in combination with Δ⁹-THC (left) or anandamide (right), in monkeys discriminating Δ⁹-THC (0.1 mg·kg⁻¹ i.v.) from vehicle. Abscissae: vehicle (V) or dose in mg·kg⁻¹ body weight. Ordinates: mean (±SEM) percentage of responding on the Δ⁹-THC lever (top) and mean (±SEM) response rate expressed as a percentage of control (V training days) rate [Rate (% control)] (bottom).

Figure 3

Time course for anandamide, alone and in combination with URB 597, in monkeys discriminating Δ⁹-THC (0.1 mg·kg⁻¹ i.v.) from vehicle. Abscissae: time in minutes. Ordinates: mean (±SEM) percentage of responding on the Δ⁹-THC lever (top) and mean (±SEM) response rate expressed as a percentage of control rate [Rate (% control)] (bottom).

Figure 4

Effects of Δ⁹-THC (left) and anandamide (right), alone and in combination with rimonabant, in Δ⁹-THC-treated (1 mg·kg⁻¹ 12 h⁻¹ s.c.) monkeys discriminating rimonabant (1 mg·kg⁻¹ i.v.). Abscissae: vehicle (V) or dose in mg·kg⁻¹ body weight of rimonabant. Ordinates: mean (±SEM) percentage of responding on the rimonabant lever (top) and mean (±SEM) response rate expressed as a percentage of control (V training days) rate [Rate (% control)] (bottom).

Figure 5

Effects of URB 597, alone (left) and in combination with anandamide (right), in Δ⁹-THC-treated (1 mg·kg⁻¹ 12 h⁻¹ s.c.) monkeys discriminating rimonabant (1 mg·kg⁻¹ i.v.). Abscissae: vehicle (V) or dose in mg·kg⁻¹ body weight of rimonabant. Ordinates: mean (±SEM) percentage of responding on the rimonabant lever (top) and mean (±SEM) response rate expressed as a percentage of control (V training days) rate [Rate (% control)] (bottom). The dashed and solid lines not connected to symbols are the effects of 10 and 32 mg·kg⁻¹ of anandamide, respectively, in combination with rimonabant, which are re-plotted from Figure 4.

Figure 6

Magnitude of rightward shift in the rimonabant dose-response function expressed as a function of dose of Δ⁹-THC, anandamide alone and anandamide plus URB 597. Abscissa: dose in mg·kg⁻¹ body weight. Ordinate: mean (±SEM) rightward shift in the rimonabant dose-response function, calculated as rimonabant ED₅₀ following pretreatment with a cannabinoid agonist divided by the control rimonabant ED₅₀.