Glutamatergic modulation of auditory information processing in the human brain.
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.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. handan.gunduz-bruce@yale.edu
Handan
H
Gunduz-Bruce
Robert M G
RM
Reinhart
Brian J
BJ
Roach
Ralitza
R
Gueorguieva
Stephen
S
Oliver
Deepak C
DC
D'Souza
Judith M
JM
Ford
John H
JH
Krystal
Daniel H
DH
Mathalon
D000111:Acetylcysteine / Q000494:pharmacology*; D000328:Adult; D001519:Behavior / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects; D004569:Electroencephalography; D018913:Event-Related Potentials, P300 / Q000187:drug effects*; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012559:Schizophrenia / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D000111:Acetylcysteine