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JWH-018 and JWH-073: Δ 9 -Tetrahydrocannabinol-Like Discriminative Stimulus Effects in Monkeys

2011; American Society for Pharmacology and Experimental Therapeutics; Volume: 340; Issue: 1 Linguagem: Inglês

10.1124/jpet.111.187757

1521-0103

Brett C. Ginsburg, David R. Schulze, Lenka Hrubá, Lance Richard McMahon,

Neurotransmitter Receptor Influence on Behavior

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 Δ 9 -tetrahydrocannabinol (Δ 9 -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 Δ 9 -THC (1 mg/kg s.c. 12 h) treatment. Δ 9 -THC, JWH-018, and JWH-073 increased drug-lever responding in monkeys discriminating Δ 9 -THC; the ED 50 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 Δ 9 -THC, JWH-018, and JWH-073. Schild analyses and single-dose apparent affinity estimates yielded apparent p A 2 /p K B values of 6.65, 6.68, and 6.79 in the presence of Δ 9 -THC, JWH-018, and JWH-073, respectively. In Δ 9 -THC-treated monkeys discriminating rimonabant, the training drug increased responding on the rimonabant lever; the ED 50 value of rimonabant was 0.20 mg/kg. Δ 9 -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 Δ 9 -THC, JWH-018, and JWH-073 act through the same receptors to produce Δ 9 -THC-like subjective effects and attenuate Δ 9 -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 Δ 9 -THC.