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γ-Aminobutyric Acid–Serotonin Interactions in Healthy Men: Implications for Network Models of Psychosis and Dissociation

  • Deepak Cyril D’Souza
    Correspondence
    Address reprint requests to: Deepak Cyril D’Souza, M.D., VA Connecticut Healthcare System 116A, Psychiatry Service, 950 Campbell Avenue, West Haven, CT 06516
    Affiliations
    Schizophrenia Biological Research Center, West Haven Veterans Affairs Medical Center, West Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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  • Roberto B. Gil
    Affiliations
    Schizophrenia Biological Research Center, West Haven Veterans Affairs Medical Center, West Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut

    Schizophrenia Research Unit, Columbia University, New York, New York
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  • Edward Zuzarte
    Affiliations
    Schizophrenia Biological Research Center, West Haven Veterans Affairs Medical Center, West Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut

    Sheppard Pratt Health System, Timonium, Maryland
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  • Lisa M. MacDougall
    Affiliations
    Schizophrenia Biological Research Center, West Haven Veterans Affairs Medical Center, West Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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  • Lia Donahue
    Affiliations
    Schizophrenia Biological Research Center, West Haven Veterans Affairs Medical Center, West Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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  • John S. Ebersole
    Affiliations
    Department of Neurology, Chicago University School of Medicine, Chicago, Illinois
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  • Nashaat N. Boutros
    Affiliations
    Schizophrenia Biological Research Center, West Haven Veterans Affairs Medical Center, West Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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  • Tom Cooper
    Affiliations
    Nathan Kline Institute, Orangeburg, New York
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  • John Seibyl
    Affiliations
    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut

    Department of Nuclear Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • John H. Krystal
    Affiliations
    Schizophrenia Biological Research Center, West Haven Veterans Affairs Medical Center, West Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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Published:September 05, 2005DOI:https://doi.org/10.1016/j.biopsych.2005.06.020

      Background

      This study tested the hypothesis that deficits in γ-aminobutyric acid type A (GABAA) receptor function might create a vulnerability to the psychotogenic and perceptual altering effects of serotonergic (5-HT2A/2C) receptor stimulation. The interactive effects of iomazenil, an antagonist and partial inverse agonist of the benzodiazepine site of the GABAA receptor complex, and m-chlorophenylpiperazine (m-CPP), a partial agonist of 5-HT2A/2C receptors, were studied in 23 healthy male subjects.

      Methods

      Subjects underwent 4 days of testing, during which they received intravenous infusions of iomazenil/placebo followed by m-CPP/placebo in a double-blind, randomized crossover design. Behavioral, cognitive, and hormonal data were collected before drug infusions and periodically for 200 min after.

      Results

      Iomazenil and m-CPP interacted in a synergistic manner to produce mild psychotic symptoms and perceptual disturbances without impairing cognition. Iomazenil and m-CPP increased anxiety in an additive fashion. Iomazenil and m-CPP interacted in a synergistic manner to increase serum cortisol.

      Conclusions

      Gamma-aminobutyric acid-ergic deficits might increase the vulnerability to the psychotomimetic and perceptual altering effects of serotonergic agents. These data suggest that interactions between GABAA and 5-HT systems might contribute to the pathophysiology of psychosis and dissociative-like perceptual states.

      Key Words

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