γ-aminobutyric acid-serotonin interactions in healthy men: Implications for network models of psychosis and dissociation

Background: This study tested the hypothesis that deficits in γ-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.