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.
Key Words
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Article info
Publication history
Published online: October 31, 2011
Accepted:
September 30,
2011
Received in revised form:
September 29,
2011
Received:
July 6,
2011
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- Translating the Rosetta Stone of N-AcetylcysteineBiological PsychiatryVol. 71Issue 11
- PreviewThe history of the field of biological psychiatry can be cynically encapsulated by the quest to reverse engineer serendipitous clinical findings. The role of monoamines in depression, dopamine in schizophrenia, and second messengers in bipolar disorder have all been reversed engineered from understanding the effects of tricyclics, antipsychotics, and lithium, respectively. In this context, the emergence of N-acetylcysteine (NAC) as a potential therapeutic modality provides a dual opportunity: a novel therapy and a key to unlocking the pathophysiology of the targeted disorders.
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