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Characterization of cannabinoid agonists and apparent pA2 analysis of cannabinoid antagonists in rhesus monkeys discriminating Delta9-tetrahydrocannabinol.

Abstract

Cannabinoid CB(1) receptors are hypothesized to mediate the discriminative stimulus effects of cannabinoids. This study characterized a Delta(9)-tetrahydrocannabinol (Delta(9)-THC; 0.1 mg/kg i.v.) discriminative stimulus and examined antagonism of cannabinoid agonists in rhesus monkeys. High levels of responding on the Delta(9)-THC lever were produced by cannabinoid agonists with the following rank order potency: CP 55940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol] > Delta(9)-THC = WIN 55212-2 [(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate salt] > arachidonylcyclopropylamide = (R)-methanandamide. A CB(2)-selective agonist, AM 1241 [(R)-3-(2-iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole], and noncannabinoids (cocaine, ketamine, midazolam, and morphine) did not produce high levels of Delta(9)-THC lever responding. The CB(1)-selective antagonist SR 141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] surmountably antagonized the discriminative stimulus effects of Delta(9)-THC and CP 55940, and Schild analysis was consistent with a simple, competitive interaction (apparent pA(2) values were 6.1 and 6.7, respectively). SR 141716A surmountably antagonized WIN 55212-2; however, larger doses disrupted responding, precluding Schild analysis. The CB(1)-selective antagonist AM 251 surmountably antagonized Delta(9)-THC, CP 55940, and WIN 55212-2, and Schild analysis was consistent with a simple, competitive interaction (apparent pA(2) values were 6.3, 6.1, and 6.2, respectively). The CB(2)-selective antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide] did not modify the Delta(9)-THC discriminative stimulus. These results demonstrate that the discriminative stimulus effects of Delta(9)-THC are selective for cannabinoid activity, and the results of Schild analysis suggest that the same receptors mediate the discriminative stimulus effects of Delta(9)-THC, CP 55940, and WIN 55212-2. CB(2) receptors do not seem to mediate the discriminative stimulus effects of cannabinoid agonists. Schild analysis has the potential for identifying receptor subtypes that mediate the in vivo effects of cannabinoid agonists.

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  • Authors+Show Affiliations

    Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. mcmahonl@uthscsa.edu

    Source

    MeSH

    Analgesics, Opioid
    Anesthetics, Dissociative
    Anesthetics, Intravenous
    Anesthetics, Local
    Animals
    Benzoxazines
    Bornanes
    Cannabinoid Receptor Agonists
    Cannabinoid Receptor Antagonists
    Cannabinoids
    Cocaine
    Cyclohexanols
    Discrimination Learning
    Dose-Response Relationship, Drug
    Dronabinol
    Female
    Hallucinogens
    Ketamine
    Macaca mulatta
    Male
    Midazolam
    Morphine
    Morpholines
    Naphthalenes
    Piperidines
    Pyrazoles
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    16943255

    Citation

    McMahon, Lance R.. "Characterization of Cannabinoid Agonists and Apparent pA2 Analysis of Cannabinoid Antagonists in Rhesus Monkeys Discriminating Delta9-tetrahydrocannabinol." The Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 3, 2006, pp. 1211-8.
    McMahon LR. Characterization of cannabinoid agonists and apparent pA2 analysis of cannabinoid antagonists in rhesus monkeys discriminating Delta9-tetrahydrocannabinol. J Pharmacol Exp Ther. 2006;319(3):1211-8.
    McMahon, L. R. (2006). Characterization of cannabinoid agonists and apparent pA2 analysis of cannabinoid antagonists in rhesus monkeys discriminating Delta9-tetrahydrocannabinol. The Journal of Pharmacology and Experimental Therapeutics, 319(3), pp. 1211-8.
    McMahon LR. Characterization of Cannabinoid Agonists and Apparent pA2 Analysis of Cannabinoid Antagonists in Rhesus Monkeys Discriminating Delta9-tetrahydrocannabinol. J Pharmacol Exp Ther. 2006;319(3):1211-8. PubMed PMID: 16943255.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Characterization of cannabinoid agonists and apparent pA2 analysis of cannabinoid antagonists in rhesus monkeys discriminating Delta9-tetrahydrocannabinol. A1 - McMahon,Lance R, Y1 - 2006/08/30/ PY - 2006/9/1/pubmed PY - 2007/1/11/medline PY - 2006/9/1/entrez SP - 1211 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 319 IS - 3 N2 - Cannabinoid CB(1) receptors are hypothesized to mediate the discriminative stimulus effects of cannabinoids. This study characterized a Delta(9)-tetrahydrocannabinol (Delta(9)-THC; 0.1 mg/kg i.v.) discriminative stimulus and examined antagonism of cannabinoid agonists in rhesus monkeys. High levels of responding on the Delta(9)-THC lever were produced by cannabinoid agonists with the following rank order potency: CP 55940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol] > Delta(9)-THC = WIN 55212-2 [(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate salt] > arachidonylcyclopropylamide = (R)-methanandamide. A CB(2)-selective agonist, AM 1241 [(R)-3-(2-iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole], and noncannabinoids (cocaine, ketamine, midazolam, and morphine) did not produce high levels of Delta(9)-THC lever responding. The CB(1)-selective antagonist SR 141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] surmountably antagonized the discriminative stimulus effects of Delta(9)-THC and CP 55940, and Schild analysis was consistent with a simple, competitive interaction (apparent pA(2) values were 6.1 and 6.7, respectively). SR 141716A surmountably antagonized WIN 55212-2; however, larger doses disrupted responding, precluding Schild analysis. The CB(1)-selective antagonist AM 251 surmountably antagonized Delta(9)-THC, CP 55940, and WIN 55212-2, and Schild analysis was consistent with a simple, competitive interaction (apparent pA(2) values were 6.3, 6.1, and 6.2, respectively). The CB(2)-selective antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide] did not modify the Delta(9)-THC discriminative stimulus. These results demonstrate that the discriminative stimulus effects of Delta(9)-THC are selective for cannabinoid activity, and the results of Schild analysis suggest that the same receptors mediate the discriminative stimulus effects of Delta(9)-THC, CP 55940, and WIN 55212-2. CB(2) receptors do not seem to mediate the discriminative stimulus effects of cannabinoid agonists. Schild analysis has the potential for identifying receptor subtypes that mediate the in vivo effects of cannabinoid agonists. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16943255/Characterization_of_cannabinoid_agonists_and_apparent_pA2_analysis_of_cannabinoid_antagonists_in_rhesus_monkeys_discriminating_Delta9_tetrahydrocannabinol_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16943255 DB - PRIME DP - Unbound Medicine ER -