1. gamma-Aminobutyric acid-serotonin interactions in healthy men: implications for network models of psychosis and dissociation.
- Author
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D'Souza DC, Gil RB, Zuzarte E, MacDougall LM, Donahue L, Ebersole JS, Boutros NN, Cooper T, Seibyl J, and Krystal JH
- Subjects
- Analysis of Variance, Anxiety chemically induced, Cross-Over Studies, Dissociative Disorders metabolism, Double-Blind Method, Drug Synergism, Flumazenil pharmacology, Humans, Male, Models, Neurological, Perceptual Disorders chemically induced, Perceptual Disorders metabolism, Receptors, GABA-A drug effects, Receptors, GABA-A metabolism, Receptors, Serotonin, 5-HT2 drug effects, Receptors, Serotonin, 5-HT2 metabolism, Reference Values, Serotonin metabolism, gamma-Aminobutyric Acid metabolism, Dissociative Disorders chemically induced, Flumazenil analogs & derivatives, GABA Modulators pharmacology, Piperazines pharmacology, Psychoses, Substance-Induced metabolism, Serotonin Receptor Agonists pharmacology
- Abstract
Background: This study tested the hypothesis that deficits in gamma-aminobutyric acid type A (GABA(A)) receptor function might create a vulnerability to the psychotogenic and perceptual altering effects of serotonergic (5-HT(2A/2C)) receptor stimulation. The interactive effects of iomazenil, an antagonist and partial inverse agonist of the benzodiazepine site of the GABA(A) receptor complex, and m-chlorophenylpiperazine (m-CPP), a partial agonist of 5-HT(2A/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 GABA(A) and 5-HT systems might contribute to the pathophysiology of psychosis and dissociative-like perceptual states.
- Published
- 2006
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