title: Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine.
abstract: Some schizophrenia patients are more sensitive to amphetamine (AMPH)-induced exacerbations in psychosis-an effect that correlates with higher striatal dopamine release. This enhanced vulnerability may be related to gamma-aminobutyric acid (GABA) deficits observed in schizophrenia. We hypothesized that a pharmacologically induced GABA deficit would create vulnerability to the psychotomimetic effects to the 'subthreshold' dose of AMPH in healthy subjects, which by itself would not induce clinically significant increase in positive symptoms. To test this hypothesis, a GABA deficit was induced by intravenous infusion of iomazenil (IOM; 3.7 μg/kg), an antagonist and partial inverse agonist of benzodiazepine receptor. A subthreshold dose of AMPH (0.1 mg/kg) was administered by intravenous infusion. Healthy subjects received placebo IOM followed by placebo AMPH, active IOM followed by placebo AMPH, placebo IOM followed by active AMPH, and active IOM followed by active AMPH in a randomized, double-blind crossover design over 4 test days. Twelve healthy subjects who had a subclinical response to active AMPH alone were included in the analysis. Psychotomimetic effects (Positive and Negative Syndrome Scale (PANSS)), perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)), and subjective effects (visual analog scale) were captured before and after the administration of drugs. IOM significantly augmented AMPH-induced peak changes in PANSS positive symptom subscale and both subjective and objective CADSS scores. There were no pharmacokinetic interactions. In conclusion, GABA deficits increased vulnerability to amphetamine-induced psychosis-relevant effects in healthy subjects, suggesting that pre-existing GABA deficits may explain why a subgroup of schizophrenia patients are vulnerable to AMPH.
authors.affiliation: Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT, USA.|Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, West Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
authors.forename: Kyung-Heup
authors.initials: KH
authors.lastname: Ahn
authors.affiliation: Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT, USA.|Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, West Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sewell
authors.affiliation: Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT, USA.|Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, West Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Elander
authors.affiliation: Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, West Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Pittman
authors.affiliation: Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT, USA.|Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, West Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
authors.forename: Mohini
authors.initials: M
authors.lastname: Ranganathan
authors.affiliation: Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
authors.forename: Handan
authors.initials: H
authors.lastname: Gunduz-Bruce
authors.affiliation: Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT, USA.|Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, West Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
authors.forename: John
authors.initials: J
authors.lastname: Krystal
authors.affiliation: Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT, USA.|Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, West Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
authors.forename: Deepak Cyril
authors.initials: DC
authors.lastname: D'Souza
mesh_terms: D000293:Adolescent; D000328:Adult; D000661:Amphetamine / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005442:Flumazenil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006213:Hallucinogens / Q000008:administration & dosage*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000209:etiology*; D013997:Time Factors; D064232:Visual Analog Scale; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000172:deficiency*
chemical_list: D006213:Hallucinogens; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C063038:iomazenil; D000661:Amphetamine