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/pKB 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.
Footnotes
This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01-DA19222, R01-DA26781].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- JWH-018
- naphthalen-1-yl-(1-pentylindol-3-yl) methanone
- JWH-073
- naphthalen-1-yl-(1-butylindol-3-yl) methanone
- Δ9-THC
- Δ9-tetrahydrocannabinol
- CB
- cannabinoid
- FR
- fixed ratio
- CL
- confidence limit
- CP 55940
- 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol
- WIN 55212-2
- (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone.
- Received September 6, 2011.
- Accepted September 29, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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