gamma-Aminobutyric acid-serotonin interactions in healthy men: implications for network models of psychosis and dissociation.
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.
D'Souza
Deepak Cyril
DC
Schizophrenia Biological Research Center, West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA. deepak.dsouza@yale.edu
Gil
Roberto B
RB
Zuzarte
Edward
E
MacDougall
Lisa M
LM
Donahue
Lia
L
Ebersole
John S
JS
Boutros
Nashaat N
NN
Cooper
Tom
T
Seibyl
John
J
Krystal
John H
JH
D000704:Analysis of Variance; D001007:Anxiety / Q000139:chemically induced; D018592:Cross-Over Studies; D004213:Dissociative Disorders / Q000139:chemically induced* / Q000378:metabolism; D004311:Double-Blind Method; D004357:Drug Synergism; D005442:Flumazenil / Q000031:analogs & derivatives* / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008959:Models, Neurological; D010468:Perceptual Disorders / Q000139:chemically induced / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011605:Psychoses, Substance-Induced / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects / Q000378:metabolism; D012016:Reference Values; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018757:GABA Modulators; D010879:Piperazines; D011963:Receptors, GABA-A; D044348:Receptors, Serotonin, 5-HT2; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C063038:iomazenil; C015068:1-(3-chlorophenyl)piperazine