Abstract

Synthetic cannabinoids have been prohibited due to abuse liability and toxicity. Four such synthetic cannabinoids, AM-2201, CP-47,497, JWH-122, and JWH-250, were tested for their capacity to produce CB1 receptor-mediated discriminative stimulus effects in two groups of rhesus monkeys. One group (n=4) discriminated ∆9-THC (0.1 mg/kg i.v.) and a second group (n=4) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) while receiving 1 mg/kg/12 h of ∆9-THC. AM-2201, JWH-122, CP-47,497, JWH-250, and ∆9-THC increased ∆9-THC-lever responding. The duration of action was 1-2 h for AM-2201, JWH-122, and JWH-250 and 4-5 h for CP-47497 and ∆9-THC. Rimonabant (1 mg/kg) surmountably antagonized the discriminative stimulus effects of all cannabinoid agonists; the magnitude of rightward shift was 10.6-fold for AM-2201, 10.7-fold for JWH-122, 11.0-fold for CP-47,497, and 15.7-fold for JWH-250. The respective pKB values were not significantly different: 6.61, 6.65, 6.66, and 6.83. In ∆9-THC treated monkeys discriminating rimonabant, AM-2201 (0.1 and 0.32 mg/kg), JWH-122 (0.32 and 1 mg/kg), JWH-250 (1 and 3.2 mg/kg), and CP-47,497 (0.32, 1, and 3.2 mg/kg) administration prior to rimonabant produced dose-dependent, parallel rightward shifts in the rimonabant discrimination dose-effect function, i.e., rimonabant significantly reversed the effects of each cannabinoid agonist. These results show striking similarity in the CB1 receptor mechanism underlying the subjective effects of AM-2201, JWH-122, JWH-250, and CP-47,497. For products containing predominantly AM-2201 and JWH-122, a short duration of action could lead to more frequent use and high potency could lead to toxicity. Rapid reversal of effects by intravenous rimonabant has potential value in emergency situations.