Discriminative Stimulus Effects and Metabolism of Ethanol in Rhesus Monkeys

Daicia C. Allen, Kathleen (Kathy) Grant

    Research output: Contribution to journalArticle

    Abstract

    Background: Animal models are an essential feature of drug and pharmacotherapy development for treating alcohol use disorders (AUDs). The rhesus macaque is a robust animal model for many aspects of AUDs particularly in exploiting individual differences in oral self-administration of ethanol (EtOH), endocrine orchestration of stress response, and menstrual cycle characteristics. However, the clearance rates of EtOH have not been reported in this species, and the GABAA and N-methyl-D-aspartate (NMDA) receptor involvement in EtOH's discriminative stimulus effects has not been fully characterized. Methods: EtOH clearance rates following 2 doses of EtOH on separate days (0.5 and 1.0 g/kg, i.g.) were determined in 8 young adult male rhesus macaques. The EtOH was given by nasogastric gavage, and repeated blood samples were taken over 5 hours without sedation. Next, all subjects were trained on a 2-choice 1.0 g/kg EtOH (i.g.) versus water discrimination with a 60-minutes pretreatment period to capture peak blood EtOH concentration (BEC). Substitution testing was conducted with GABAA ligands pentobarbital (i.g. and i.m.) and midazolam (i.g.), as well as NMDA antagonist MK-801 (i.m.). Results: Peak BECs were 34 and 87 mg/dl for 0.5 and 1.0 g/kg doses, respectively, and occurred at 66 and 87 minutes following gavage. All GABAA and NMDA ligands tested resulted in responding on the EtOH-appropriate lever with the potency ranking of MK-801 (ED50: 0.017 mg/kg) > midazolam (ED50: 1.6 mg/kg) > pentobarbital (ED50: 3.7 mg/kg) > EtOH (ED50: 700 mg/kg, or 0.7 g/kg) in these subjects. Conclusions: These results suggest that the compound discriminative stimulus effects of EtOH are highly consistent across species, providing further support for the rhesus macaque as strong model for pharmacotherapy development for AUD.

    Original languageEnglish (US)
    JournalAlcoholism: Clinical and Experimental Research
    DOIs
    StatePublished - Jan 1 2019

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    Macaca mulatta
    Metabolism
    Drug therapy
    Ethanol
    Dizocilpine Maleate
    Midazolam
    Alcohols
    Pentobarbital
    N-Methylaspartate
    Animals
    Blood
    Animal Models
    Essential Drugs
    Ligands
    Drug Therapy
    Self Administration
    Menstrual Cycle
    N-Methyl-D-Aspartate Receptors
    Individuality
    Oral Administration

    Keywords

    • Drug Discrimination
    • Ethanol
    • Ethanol Clearance
    • Macaque

    ASJC Scopus subject areas

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

    Cite this

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    title = "Discriminative Stimulus Effects and Metabolism of Ethanol in Rhesus Monkeys",
    abstract = "Background: Animal models are an essential feature of drug and pharmacotherapy development for treating alcohol use disorders (AUDs). The rhesus macaque is a robust animal model for many aspects of AUDs particularly in exploiting individual differences in oral self-administration of ethanol (EtOH), endocrine orchestration of stress response, and menstrual cycle characteristics. However, the clearance rates of EtOH have not been reported in this species, and the GABAA and N-methyl-D-aspartate (NMDA) receptor involvement in EtOH's discriminative stimulus effects has not been fully characterized. Methods: EtOH clearance rates following 2 doses of EtOH on separate days (0.5 and 1.0 g/kg, i.g.) were determined in 8 young adult male rhesus macaques. The EtOH was given by nasogastric gavage, and repeated blood samples were taken over 5 hours without sedation. Next, all subjects were trained on a 2-choice 1.0 g/kg EtOH (i.g.) versus water discrimination with a 60-minutes pretreatment period to capture peak blood EtOH concentration (BEC). Substitution testing was conducted with GABAA ligands pentobarbital (i.g. and i.m.) and midazolam (i.g.), as well as NMDA antagonist MK-801 (i.m.). Results: Peak BECs were 34 and 87 mg/dl for 0.5 and 1.0 g/kg doses, respectively, and occurred at 66 and 87 minutes following gavage. All GABAA and NMDA ligands tested resulted in responding on the EtOH-appropriate lever with the potency ranking of MK-801 (ED50: 0.017 mg/kg) > midazolam (ED50: 1.6 mg/kg) > pentobarbital (ED50: 3.7 mg/kg) > EtOH (ED50: 700 mg/kg, or 0.7 g/kg) in these subjects. Conclusions: These results suggest that the compound discriminative stimulus effects of EtOH are highly consistent across species, providing further support for the rhesus macaque as strong model for pharmacotherapy development for AUD.",
    keywords = "Drug Discrimination, Ethanol, Ethanol Clearance, Macaque",
    author = "Allen, {Daicia C.} and Grant, {Kathleen (Kathy)}",
    year = "2019",
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    day = "1",
    doi = "10.1111/acer.14142",
    language = "English (US)",
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    TY - JOUR

    T1 - Discriminative Stimulus Effects and Metabolism of Ethanol in Rhesus Monkeys

    AU - Allen, Daicia C.

    AU - Grant, Kathleen (Kathy)

    PY - 2019/1/1

    Y1 - 2019/1/1

    N2 - Background: Animal models are an essential feature of drug and pharmacotherapy development for treating alcohol use disorders (AUDs). The rhesus macaque is a robust animal model for many aspects of AUDs particularly in exploiting individual differences in oral self-administration of ethanol (EtOH), endocrine orchestration of stress response, and menstrual cycle characteristics. However, the clearance rates of EtOH have not been reported in this species, and the GABAA and N-methyl-D-aspartate (NMDA) receptor involvement in EtOH's discriminative stimulus effects has not been fully characterized. Methods: EtOH clearance rates following 2 doses of EtOH on separate days (0.5 and 1.0 g/kg, i.g.) were determined in 8 young adult male rhesus macaques. The EtOH was given by nasogastric gavage, and repeated blood samples were taken over 5 hours without sedation. Next, all subjects were trained on a 2-choice 1.0 g/kg EtOH (i.g.) versus water discrimination with a 60-minutes pretreatment period to capture peak blood EtOH concentration (BEC). Substitution testing was conducted with GABAA ligands pentobarbital (i.g. and i.m.) and midazolam (i.g.), as well as NMDA antagonist MK-801 (i.m.). Results: Peak BECs were 34 and 87 mg/dl for 0.5 and 1.0 g/kg doses, respectively, and occurred at 66 and 87 minutes following gavage. All GABAA and NMDA ligands tested resulted in responding on the EtOH-appropriate lever with the potency ranking of MK-801 (ED50: 0.017 mg/kg) > midazolam (ED50: 1.6 mg/kg) > pentobarbital (ED50: 3.7 mg/kg) > EtOH (ED50: 700 mg/kg, or 0.7 g/kg) in these subjects. Conclusions: These results suggest that the compound discriminative stimulus effects of EtOH are highly consistent across species, providing further support for the rhesus macaque as strong model for pharmacotherapy development for AUD.

    AB - Background: Animal models are an essential feature of drug and pharmacotherapy development for treating alcohol use disorders (AUDs). The rhesus macaque is a robust animal model for many aspects of AUDs particularly in exploiting individual differences in oral self-administration of ethanol (EtOH), endocrine orchestration of stress response, and menstrual cycle characteristics. However, the clearance rates of EtOH have not been reported in this species, and the GABAA and N-methyl-D-aspartate (NMDA) receptor involvement in EtOH's discriminative stimulus effects has not been fully characterized. Methods: EtOH clearance rates following 2 doses of EtOH on separate days (0.5 and 1.0 g/kg, i.g.) were determined in 8 young adult male rhesus macaques. The EtOH was given by nasogastric gavage, and repeated blood samples were taken over 5 hours without sedation. Next, all subjects were trained on a 2-choice 1.0 g/kg EtOH (i.g.) versus water discrimination with a 60-minutes pretreatment period to capture peak blood EtOH concentration (BEC). Substitution testing was conducted with GABAA ligands pentobarbital (i.g. and i.m.) and midazolam (i.g.), as well as NMDA antagonist MK-801 (i.m.). Results: Peak BECs were 34 and 87 mg/dl for 0.5 and 1.0 g/kg doses, respectively, and occurred at 66 and 87 minutes following gavage. All GABAA and NMDA ligands tested resulted in responding on the EtOH-appropriate lever with the potency ranking of MK-801 (ED50: 0.017 mg/kg) > midazolam (ED50: 1.6 mg/kg) > pentobarbital (ED50: 3.7 mg/kg) > EtOH (ED50: 700 mg/kg, or 0.7 g/kg) in these subjects. Conclusions: These results suggest that the compound discriminative stimulus effects of EtOH are highly consistent across species, providing further support for the rhesus macaque as strong model for pharmacotherapy development for AUD.

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    KW - Macaque

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