Effects of nicotine on the neurophysiological and behavioral effects of ketamine in humans.
BACKGROUND
N-methyl-d-aspartate (NMDA) receptor hypofunction has been implicated in the pathophysiology of schizophrenia and its associated neurocognitive impairments. The high rate of cigarette smoking in schizophrenia raises questions about how nicotine modulates putative NMDA receptor hypofunction in the illness. Accordingly, we examined the modulatory effects of brain nicotinic acetylcholine receptor (nAChR) stimulation on NMDA receptor hypofunction by examining the interactive effects of nicotine, a nAChR agonist, and ketamine, a non-competitive NMDA receptor antagonist, on behavioral and neurophysiological measures in healthy human volunteers.


METHODS
From an initial sample of 17 subjects (age range 18-55 years), 8 subjects successfully completed 4 test sessions, each separated by at least 3 days, during which they received ketamine or placebo and two injections of nicotine or placebo in a double-blind, counterbalanced manner. Schizophrenia-like effects Positive and Negative Syndrome Scale, perceptual alterations Clinician Administered Dissociative Symptoms Scale, subjective effects Visual Analog Scale and auditory event-related brain potentials (mismatch negativity, MMN; P300) were assessed during each test session.


RESULTS
Consistent with existing studies, ketamine induced transient schizophrenia-like behavioral effects. P300 was reduced and delayed by ketamine regardless of whether it was elicited by a target (P3b) or novel (P3a) stimulus, while nicotine only reduced the amplitude of P3a. Nicotine did not rescue P300 from the effects of ketamine; the interactions of ketamine and nicotine were not significant. While nicotine significantly reduced MMN amplitude, ketamine did not.


CONCLUSIONS
Nicotine failed to modulate ketamine-induced neurophysiological and behavioral effects in this preliminary study. Interestingly, ketamine reduced P3b amplitude and nicotine reduced P3a amplitude, suggesting independent roles of NMDA receptor and nAChR in the generation of P3b and P3a, respectively.
Department of Psychiatry, University of California San Francisco , San Francisco, CA , USA ; Mental Health Service (116D), San Francisco VA Medical Center , San Francisco, CA , USA.
Daniel H
DH
Mathalon
Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; Schizophrenia Biological Research Center (116A), VA Connecticut Healthcare System , West Haven, CT , USA ; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center , New Haven, CT , USA.
Kyung-Heup
KH
Ahn
Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; Schizophrenia Biological Research Center (116A), VA Connecticut Healthcare System , West Haven, CT , USA ; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center , New Haven, CT , USA.
Edward B
EB
Perry
Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; Department of Psychiatry, Yonsei University College of Medicine , Seoul , South Korea.
Hyun-Sang
HS
Cho
Mental Health Service (116D), San Francisco VA Medical Center , San Francisco, CA , USA.
Brian J
BJ
Roach
Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA.
Rebecca K
RK
Blais
Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA.
Savita
S
Bhakta
Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA.
Mohini
M
Ranganathan
Department of Psychiatry, University of California San Francisco , San Francisco, CA , USA ; Mental Health Service (116D), San Francisco VA Medical Center , San Francisco, CA , USA.
Judith M
JM
Ford
Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; Schizophrenia Biological Research Center (116A), VA Connecticut Healthcare System , West Haven, CT , USA ; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center , New Haven, CT , USA.
Deepak Cyril
DC
D'Souza
N-methyl-d-aspartate receptor; P300; event-related potential; ketamine; mismatch negativity; nicotine; nicotinic acetylcholine receptor; schizophrenia