Antagonism of the ethanol-like discriminative stimulus effects of ethanol, pentobarbital, and midazolam in cynomolgus monkeys reveals involvement of specific GABAA receptor subtypes

Christa M. Helms, Laura S.M. Rogers, Kathleen A. Grant

    Research output: Contribution to journalArticlepeer-review

    13 Scopus citations

    Abstract

    The γ-aminobutyric acid (GABA)A receptors mediating the discriminative stimulus effects of ethanol were studied by comparing the potency of ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4Himidazol( 1,5-a)benzodiazepine-3- carboxylate (Ro15-4513) and ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H- imidazol(1,5-a)-benzodiazepine-3-carboxylate (flumazenil, Ro15-1788) to antagonize ethanol, pentobarbital (PB), and midazolam substitution for ethanol. Ro15-4513 has high affinity for receptors containing α4/6 and α5 subunits and lower affinity for α1, α2, and α3 subunits. Flumazenil is nonselective for GABAA receptors containing α1, α2, α3, and α5 subunits and has low affinity for α4/6-containing receptors. Male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) were trained to discriminate ethanol (1.0 or 2.0 g/kg i.g., 30-min pretreatment) from water. Ethanol, PB, and midazolam dose-dependently substituted for ethanol (80% ethanol-appropriate responding). Ro15-4513 (0.003-0.56 mg/kg i.m., 5-min pretreatment) shifted the ethanol, PB, and midazolam doseresponse functions rightward in a vast majority of monkeys tested (15/15, 16/17, and 11/12, respectively). In contrast, flumazenil (0.30-10.0 mg/kg i.m., 5-min pretreatment) shifted the ethanol, PB, and midazolam dose-response functions rightward in 9 of 16, 12 of 16, and 7 of 9 monkeys tested, respectively. In the monkeys showing antagonism with both Ro15-4513 and flumazenil, ethanol and PB substitution were antagonized more potently by Ro15-4513 than by flumazenil, whereas midazolam substitution was antagonized with similar potency. There were no sex or training dose differences, with the exception that flumazenil failed to antagonize ethanol substitution in males trained to discriminate 2.0 g/kg ethanol. GABAA receptors with high affinity for Ro15-4513 (i.e., containing α4/6 and α5 subunits) may be particularly important mediators of the multiple discriminative stimulus effects of ethanol through GABAA receptor systems.

    Original languageEnglish (US)
    Pages (from-to)142-152
    Number of pages11
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume331
    Issue number1
    DOIs
    StatePublished - Oct 2009

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology

    Fingerprint Dive into the research topics of 'Antagonism of the ethanol-like discriminative stimulus effects of ethanol, pentobarbital, and midazolam in cynomolgus monkeys reveals involvement of specific GABA<sub>A</sub> receptor subtypes'. Together they form a unique fingerprint.

    Cite this