TY - JOUR
T1 - The cannabinoid agonist HU-210
T2 - Pseudo-irreversible discriminative stimulus effects in rhesus monkeys
AU - Hruba, Lenka
AU - McMahon, Lance R.
N1 - Funding Information:
The authors are grateful to A. Zaki and D. Schulze for technical assistance. This work was supported by the National Institutes of Health National Institute on Drug Abuse [ DA19222 ].
PY - 2014/3/15
Y1 - 2014/3/15
N2 - 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.
AB - 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.
KW - Apparent affinity
KW - Cannabinoid
KW - Drug discrimination
KW - HU-210
KW - Pseudo-irreversible
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U2 - 10.1016/j.ejphar.2014.01.041
DO - 10.1016/j.ejphar.2014.01.041
M3 - Article
C2 - 24486701
AN - SCOPUS:84893665337
VL - 727
SP - 35
EP - 42
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1
ER -