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 Δ(9)-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 ∆(9)-THC (0.1mg/kg i.v.); a separate group received chronic ∆(9)-THC (1mg/kg/12h s.c.) and discriminated rimonabant (1mg/kg i.v.). CP 55,940, HU-210, ∆(9)-THC, and WIN 55,212-2 produced ∆(9)-THC lever responding. HU-210 had a long duration (i.e., 1-2 days), whereas that of the other cannabinoids was 5h or less. Rimonabant (1mg/kg) produced surmountable antagonism; single dose-apparent affinity estimates determined in the presence of ∆(9)-THC, CP 55,940, and WIN 55,212-2 did not differ from each other. In contrast, rimonabant (1mg/kg) produced a smaller rightward shift in the HU-210 dose-effect function. In ∆(9)-THC treated monkeys, the relative potency of CP 55,940, ∆(9)-THC, and WIN 55,212-2 to attenuate the discriminative stimulus effects of rimonabant was the same as that evidenced in the ∆(9)-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 ∆(9)-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.
Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, United States.
Lenka
L
Hruba
Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, United States. Electronic address: mcmahonl@uthscsa.edu.
Lance R
LR
McMahon
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists; D003511:Cyclohexanols / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000187:drug effects* / Q000378:metabolism; D000077285:Rimonabant; D013997:Time Factors
D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C062018:HU 211; D000077285:Rimonabant
Apparent affinity; Cannabinoid; Drug discrimination; HU-210; Pseudo-irreversible