JWH-018 and JWH-073: Δ⁹-tetrahydrocannabinol-like discriminative stimulus effects in monkeys

Abstract

Products containing naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073) are emerging drugs of abuse. Here, the behavioral effects of JWH-018 and JWH-073 were examined in one behavioral assay selective for cannabinoid agonism, rhesus monkeys (n = 4) discriminating Δ⁹-tetrahydrocannabinol (Δ⁹-THC; 0.1 mg/kg i.v.), and another assay sensitive to cannabinoid withdrawal, i.e., monkeys (n = 3) discriminating the cannabinoid antagonist rimonabant (1 mg/kg i.v.) during chronic Δ⁹-THC (1 mg/kg s.c. 12 h) treatment. Δ⁹-THC, JWH-018, and JWH-073 increased drug-lever responding in monkeys discriminating Δ⁹-THC; the ED₅₀ values were 0.044, 0.013, and 0.058 mg/kg, respectively and the duration of action was 4, 2, and 1 h, respectively. Rimonabant (0.32-3.2 mg/kg) produced surmountable antagonism of Δ⁹-THC, JWH-018, and JWH-073. Schild analyses and single-dose apparent affinity estimates yielded apparent pA₂/pK(B) values of 6.65, 6.68, and 6.79 in the presence of Δ⁹-THC, JWH-018, and JWH-073, respectively. In Δ⁹-THC-treated monkeys discriminating rimonabant, the training drug increased responding on the rimonabant lever; the ED₅₀ value of rimonabant was 0.20 mg/kg. Δ⁹-THC (1-10 mg/kg), JWH-018 (0.32-3.2 mg/kg), and JWH-073 (3.2-32 mg/kg) dose-dependently attenuated the rimonabant-discriminative stimulus (i.e., withdrawal). These results suggest that Δ⁹-THC, JWH-018, and JWH-073 act through the same receptors to produce Δ⁹-THC-like subjective effects and attenuate Δ⁹-THC withdrawal. The relatively short duration of action of JWH-018 and JWH-073 might lead to more frequent use, which could strengthen habitual use by increasing the frequency of stimulus-outcome pairings. This coupled with the possible greater efficacy of JWH-018 at cannabinoid 1 receptors could be associated with greater dependence liability than Δ⁹-THC.

Fig. 1.

Discriminative stimulus effects of Δ⁹-THC, JWH-018, and JWH-073 as a function of dose (left) and time (right). Abscissae: vehicle or dose in milligram per kilogram of body weight (left) and time in hours (right). Ordinates: mean (± S.E.M.) percentage of responding on the Δ⁹-THC lever (top) and mean (± S.E.M.) response rate expressed as a percentage of control (VEH training days) rate [rate (% control)] (bottom).

Fig. 2.

Discriminative stimulus effects of Δ⁹-THC (left), JWH-018 (center), and JWH-073 (right): antagonism by rimonabant. Abscissae: dose in milligram per kilogram of body weight or vehicle (VEH). Ordinates: mean (± S.E.M.) percentage of responses on the Δ⁹-THC lever (top) and mean (± S.E.M.) response rate expressed as a percentage of control (VEH training days) rate [rate (% control)]. The control dose-response curves for Δ⁹-THC, JWH-018, and JWH-073 are replotted from Fig. 1.

Fig. 3.

Schild plots for Δ⁹-THC (top) and JWH-018 (middle) and a log (DR-1) value for JWH-073 (bottom) constructed from the mean data shown in Fig. 2. Abscissae: negative logarithm of the dose in moles per kilogram. Ordinates: mean (± S.E.M.) logarithm of the dose ratio −1. Schild plots were constructed from the unconstrained slopes (dashed lines) and by constraining the slopes to −1 (solid lines).

Fig. 4.

Discriminative stimulus effects of rimonabant: attenuation by Δ⁹-THC (left), JWH-018 (center), and JWH-073 (right). Abscissae: dose of rimonabant in milligram per kilogram of body weight or vehicle (VEH). Ordinates: mean (± S.E.M.) percentage of responses on the rimonabant lever (top) and mean (± S.E.M.) response rate expressed as a percentage of control (VEH training days) rate [rate (% control)] (bottom). The control dose-response curve for rimonabant is the same in each panel.

Fig. 5.

Magnitude of rightward shift in the rimonabant dose-response function expressed as a function of JWH-018, Δ⁹-THC, and JWH-073 dose. Abscissa: dose in milligram per kilogram of body weight. Ordinate: mean (± S.E.M.) rightward shift in the rimonabant dose-response function, calculated as the rimonabant ED₅₀ value after pretreatment with a cannabinoid agonist divided by the control rimonabant ED₅₀ value.