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Schizophr Res. 2018 Jan;191:87-94. doi: 10.1016/j.schres.2017.06.040. Epub 2017 Jul 12.

Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia.

Author information

1
San Francisco VA Health Care System, 4150 Clement St 116D, San Francisco, CA 94121, USA; University of California, San Francisco, 401 Parnassus Ave, San Francisco, CA 94143, USA.
2
Veterans Affairs Connecticut Health Care System, 950 Campbell Ave, 116A, West Haven, CT 06516, USA; Yale University, 300 George St, Suite 901, New Haven, CT 06511, USA.
3
Northern California Institute for Research and Education, 4150 Clement St, San Francisco, CA 94121, USA.
4
University of California, San Francisco, 401 Parnassus Ave, San Francisco, CA 94143, USA.
5
Yale University, 300 George St, Suite 901, New Haven, CT 06511, USA; Now at University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA.
6
Yale University, 300 George St, Suite 901, New Haven, CT 06511, USA.
7
San Francisco VA Health Care System, 4150 Clement St 116D, San Francisco, CA 94121, USA; University of California, San Francisco, 401 Parnassus Ave, San Francisco, CA 94143, USA. Electronic address: daniel.mathalon@ucsf.edu.

Abstract

N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction has been implicated in the pathophysiology of schizophrenia, including auditory processing abnormalities reflected by the mismatch negativity (MMN) event-related potential component. Evidence suggesting cognitive benefits from nicotine administration, together with the high rate of cigarette use in patients with schizophrenia, has stimulated interest in whether nicotine modulates NMDAR hypofunction. We examined the interactive effects of ketamine, an NMDAR antagonist that produces transient schizophrenia-like neurophysiological effects, and nicotine, a nicotinic acetylcholine receptor (nAChR) agonist, in 30 healthy volunteers to determine whether nicotine prevents or attenuates MMN abnormalities. Secondary analyses compared the profile of ketamine and schizophrenia effects on MMN using previously reported data from 24 schizophrenia patients (Hay et al. 2015). Healthy volunteers completed four test days, during which they received ketamine/placebo and nicotine/placebo in a double-blind, counterbalanced design. MMN to intensity, frequency, duration, and frequency+duration double deviant sounds was assessed each day. Ketamine decreased intensity, frequency, and double deviant MMN amplitudes, whereas nicotine increased intensity and double deviant MMN amplitudes. A ketamine√ónicotine interaction indicated, however, that nicotine failed to attenuate the decrease in MMN associated with ketamine. Although the present dose of ketamine produced smaller decrements in MMN than those associated with schizophrenia, the profile of effects across deviant types did not differ between ketamine and schizophrenia. Results suggest that while ketamine and schizophrenia produce similar profiles of MMN effects across deviant types, nicotinic agonists may have limited potential to improve these putative NMDAR hypofunction-mediated impairments in schizophrenia.

KEYWORDS:

Electroencephalography; Ketamine; Mismatch negativity; NMDAR hypofunction; Nicotine; Schizophrenia

PMID:
28711472
PMCID:
PMC5745273
[Available on 2019-01-01]
DOI:
10.1016/j.schres.2017.06.040

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