Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol

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

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    10 Scopus citations

    Abstract

    Background: The subtypes of γ-aminobutyric acid (GABA) A receptors mediating the discriminative stimulus effects of ethanol in nonhuman primates are not completely identified. The GABA A receptor positive modulator zolpidem has high, intermediate, and low activity at receptors containing α 1, α 2/3, and α 5 subunits, respectively, and partially generalizes from ethanol in several species. The partial inverse agonist Ro15-4513 has the greatest affinity for α 4/6-containing receptors, higher affinity for α 5- and lower, but equal, affinity for α 1- and α 2/3-, containing GABA A receptors, and antagonizes the discriminative stimulus effects of ethanol. Methods: This study assessed Ro15-4513 antagonism of the generalization of zolpidem from ethanol in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 g/kg (n = 10) or 2.0 g/kg (n = 7) ethanol (i.g.) from water with a 30-minute pretreatment interval. Results: Zolpidem (0.017 to 5.6 mg/kg, i.m.) completely generalized from ethanol (≥80% of total session responses on the ethanol-appropriate lever) for 6/7 monkeys trained to discriminate 2.0 g/kg and 4/10 monkeys trained to discriminate 1.0 g/kg ethanol. Zolpidem partially generalized from 1.0 or 2.0 g/kg ethanol in 6/7 remaining monkeys. Ro15-4513 (0.003 to 0.30 mg/kg, i.m., 5-minute pretreatment) shifted the zolpidem dose-response curve to the right in all monkeys showing generalization. Analysis of apparent pK B from antagonism tests suggested that the discriminative stimulus effects of ethanol common with zolpidem are mediated by low-affinity Ro1 5-4513 binding sites. Main effects of sex and training dose indicated greater potency of Ro15-4513 in males and in monkeys trained to discriminate 1.0 g/kg ethanol. Conclusions: Ethanol and zolpidem share similar discriminative stimulus effects most likely through GABA A receptors that contain α 1 subunits, however, antagonism by Ro15-4513 of zolpidem generalization from the lower training dose of ethanol (1.0 g/kg) may involve additional zolpidem-sensitive GABA A receptor subtypes (e.g., α 2/3 and α 5).

    Original languageEnglish (US)
    Pages (from-to)1197-1206
    Number of pages10
    JournalAlcoholism: Clinical and Experimental Research
    Volume32
    Issue number7
    DOIs
    StatePublished - Jul 1 2008

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    Keywords

    • Cynomolgus Monkeys
    • Drug Discrimination
    • Ethanol
    • Ro15-4513
    • Zolpidem

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Toxicology
    • Psychiatry and Mental health

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