The cannabinoid agonist HU-210: Pseudo-irreversible discriminative stimulus effects in rhesus monkeys

Synthetic cannabinoid abuse and case reports of adverse effects have raised concerns about the pharmacologic mechanisms underlying in vivo effects. Here, a synthetic cannabinoid identified in abused products (HU-210) was compared to the effects of Δ⁹-THC and two other synthetic cannabinoid agonists used extensively in pre-clinical studies (CP 55,940 and WIN 55,212-2). One group of monkeys discriminated δ⁹-THC (0.1 mg/kg i.v.); a separate group received chronic δ⁹-THC (1 mg/kg/12 h s.c.) and discriminated rimonabant (1 mg/kg i.v.). CP 55,940, HU-210, δ⁹- THC, and WIN 55,212-2 produced δ⁹-THC lever responding. HU-210 had a long duration (i.e., 1-2 days), whereas that of the other cannabinoids was 5 h or less. Rimonabant (1 mg/kg) produced surmountable antagonism; single dose-apparent affinity estimates determined in the presence of δ⁹-THC, CP 55,940, and WIN 55,212-2 did not differ from each other. In contrast, rimonabant (1 mg/kg) produced a smaller rightward shift in the HU-210 dose-effect function. In δ⁹-THC treated monkeys, the relative potency of CP 55,940, δ⁹-THC, and WIN 55,212-2 to attenuate the discriminative stimulus effects of rimonabant was the same as that evidenced in the δ⁹-THC discrimination, whereas HU-210 was unexpectedly more potent in attenuating the effects of rimonabant. In conclusion, the same receptor subtype mediates the discriminative stimulus effects of δ⁹-THC, CP 55,940 and WIN 55,212-2. The limited effectiveness of rimonabant to either prevent or reverse the effects of HU-210 appears to be due to very slow dissociation or pseudo-irreversible binding of HU-210 at cannabinoid receptors.