Glutamatergic modulation of auditory information processing in the human brain

Biol Psychiatry. 2012 Jun 1;71(11):969-77. doi: 10.1016/j.biopsych.2011.09.031. Epub 2011 Oct 29.

Abstract

Background: Auditory mismatch negativity (MMN) and P300 event-related potentials (ERPs) are reduced in schizophrenia patients and healthy volunteers administered the N-methyl-D-aspartate glutamate receptor antagonist, ketamine. In rodents, N-acetylcysteine (NAC), a stimulator of the cystine-glutamate exchanger, attenuates the cognitive and behavioral effects of N-methyl-D-aspartate receptor antagonists. On the basis of these findings, we tested whether NAC would reduce ketamine effects on behavior, MMN, and P300 in healthy humans.

Methods: This randomized, double-blind, placebo-controlled study consisted of 2 test days during which subjects (n = 16) were administered oral NAC (3000 mg in divided doses) or matching placebo 165 min before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Behavioral and ERP data including auditory MMN and P300 were collected during each test day.

Results: Ketamine produced psychotic-like positive symptoms, reductions in working memory and sustained attention performance, and amplitude reductions for the frequency- and intensity-deviant MMNs and P300. NAC pretreatment did not reduce the behavioral or ERP effects of ketamine. In addition, NAC reduced frequency-deviant MMN amplitude and increased target and novelty P3 amplitudes. The decrements in frequency-deviant MMN amplitude produced by ketamine and NAC were not additive.

Conclusions: NAC did not attenuate the effects of ketamine in humans, in contrast to previous studies in animals. NAC merits further investigation as a cognitive enhancing agent due to its ability to increase the P300 amplitude.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcysteine / pharmacology*
  • Adult
  • Behavior / drug effects*
  • Cognition / drug effects
  • Electroencephalography
  • Event-Related Potentials, P300 / drug effects*
  • Evoked Potentials, Auditory / drug effects*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Free Radical Scavengers / pharmacology*
  • Humans
  • Ketamine / pharmacology*
  • Male
  • Memory / drug effects
  • Psychomotor Performance / drug effects
  • Reaction Time / drug effects
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Schizophrenia / physiopathology

Substances

  • Excitatory Amino Acid Antagonists
  • Free Radical Scavengers
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • Acetylcysteine