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The cannabinoid agonist HU-210: pseudo-irreversible discriminative stimulus effects in rhesus monkeys.
Eur J Pharmacol 2014; 727:35-42EJ

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.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, United States.Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, United States. Electronic address: mcmahonl@uthscsa.edu.

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24486701

Citation

Hruba, Lenka, and Lance R. McMahon. "The Cannabinoid Agonist HU-210: Pseudo-irreversible Discriminative Stimulus Effects in Rhesus Monkeys." European Journal of Pharmacology, vol. 727, 2014, pp. 35-42.
Hruba L, McMahon LR. The cannabinoid agonist HU-210: pseudo-irreversible discriminative stimulus effects in rhesus monkeys. Eur J Pharmacol. 2014;727:35-42.
Hruba, L., & McMahon, L. R. (2014). The cannabinoid agonist HU-210: pseudo-irreversible discriminative stimulus effects in rhesus monkeys. European Journal of Pharmacology, 727, pp. 35-42. doi:10.1016/j.ejphar.2014.01.041.
Hruba L, McMahon LR. The Cannabinoid Agonist HU-210: Pseudo-irreversible Discriminative Stimulus Effects in Rhesus Monkeys. Eur J Pharmacol. 2014 Mar 15;727:35-42. PubMed PMID: 24486701.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The cannabinoid agonist HU-210: pseudo-irreversible discriminative stimulus effects in rhesus monkeys. AU - Hruba,Lenka, AU - McMahon,Lance R, Y1 - 2014/01/30/ PY - 2013/10/01/received PY - 2014/01/14/revised PY - 2014/01/22/accepted PY - 2014/2/4/entrez PY - 2014/2/4/pubmed PY - 2015/1/30/medline KW - Apparent affinity KW - Cannabinoid KW - Drug discrimination KW - HU-210 KW - Pseudo-irreversible SP - 35 EP - 42 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 727 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 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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/24486701/The_cannabinoid_agonist_HU_210:_pseudo_irreversible_discriminative_stimulus_effects_in_rhesus_monkeys_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(14)00071-5 DB - PRIME DP - Unbound Medicine ER -