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

Eur J Pharmacol. 2014 Mar 15;727:35-42. doi: 10.1016/j.ejphar.2014.01.041. Epub 2014 Jan 30.

Abstract

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.

Keywords: Apparent affinity; Cannabinoid; Drug discrimination; HU-210; Pseudo-irreversible.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Benzoxazines / pharmacology
  • Cannabinoid Receptor Agonists / metabolism
  • Cannabinoid Receptor Agonists / pharmacology*
  • Cannabinoid Receptor Antagonists
  • Cyclohexanols / pharmacology
  • Discrimination, Psychological / drug effects*
  • Dose-Response Relationship, Drug
  • Dronabinol / analogs & derivatives*
  • Dronabinol / metabolism
  • Dronabinol / pharmacology
  • Female
  • Macaca mulatta
  • Male
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptors, Cannabinoid / drug effects*
  • Receptors, Cannabinoid / metabolism
  • Rimonabant
  • Time Factors

Substances

  • Benzoxazines
  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Cyclohexanols
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptors, Cannabinoid
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Dronabinol
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • HU 211
  • Rimonabant