Cross-substitution of Δ9-tetrahydrocannabinol and JWH-018 in drug discrimination in rats

Abstract

Synthetic indole-derived cannabinoids, originally developed to probe cannabinoid CB1 and CB2 receptors, have become widely abused for their marijuana-like intoxicating properties. The present study examined the effects of indole-derived cannabinoids in rats trained to discriminate Δ(9)-tetrahydrocannabinol (Δ(9)-THC) from vehicle. In addition, the effects of Δ(9)-THC in rats trained to discriminate JWH-018 from vehicle were assessed. Adult male Sprague-Dawley rats were trained to discriminate 3mg/kg Δ(9)-THC or 0.3mg/kg JWH-018 from vehicle. JWH-018, JWH-073, and JWH-210 fully substituted in Δ(9)-THC-trained rats and Δ(9)-THC substituted in JWH-018-trained rats. In contrast, JWH-320, an indole-derived cannabinoid without affinity for CB1 receptors, failed to substitute for Δ(9)-THC. Pre-treatment with 1mg/kg rimonabant significantly reduced responding on the JWH-018-associated lever in JWH-018-trained rats. These results support the conclusion that the interoceptive effects of Δ(9)-THC and synthetic indole-derived cannabinoids show a large degree of overlap, which is predictive of their use for their marijuana-like intoxicating properties. Characterization of the extent of pharmacological differences among structural classes of cannabinoids, and determination of their mechanisms remain important goals.

Keywords: Discriminative stimulus; JWH-018; JWH-073; JWH-210; Synthetic cannabinoids; Δ(9)-tetrahydrocannabinol.

Figure 1

Chemical structures of JWH-018, JWH-073, JWH-210, and JWH-320.

Figure 2

Panel A shows the effects of Δ⁹-THC and JWH-018 on percentage of Δ⁹-THC-lever responding in rats trained to discriminate 3 mg/kg Δ⁹-THC from vehicle. Response rates for these dose-effect curves are shown in panel B. Panel C shows the effects of JWH-073, JWH-210, and JWH-320 in the same group of Δ⁹-THC-trained rats. For ease of comparison, results of Δ⁹-THC are presented again (in greytone). Response rates for these dose-effect curves are shown in panel D. Panel E presents the effects of JWH-018 and Δ⁹-THC on percentage of JWH-018-lever responding in rats trained to discriminate 0.3 mg/kg JWH-018 from vehicle. Results of an antagonist test with 1 mg/kg rimonabant and the training dose (0.3 mg/kg) of JWH-018 are also shown. Response rates for these tests are shown in panel F. In panels A–D, points above V and T represent the results of control tests with vehicle and 3 mg/kg Δ⁹-THC conducted before each dose-effect determination. In panels E–F, points above V and J represent the results of control tests with vehicle and 0.3 mg/kg JWH-018. For each dose-effect curve determination, values represent the mean (± SEM) of 7–8 rats, except as indicated by numbers in parentheses in the panels. For agonist tests, asterisk (*) indicates a significant difference in response rates (p < 0.05) relative to the vehicle condition. For the antagonist test (panel E), number sign (#) indicates a significant difference (p < 0.05) of JWH-018 plus rimonabant, relative to vehicle and to JWH-018 tested alone.