Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia
Introduction
A cornerstone of the glutamatergic N-methyl-d-aspartate receptor (NMDAR) hypofunction model of schizophrenia is evidence that NMDAR antagonists such as ketamine induce symptoms, neurocognitive deficits, and neurophysiological abnormalities similar to those observed in schizophrenia (Krystal et al., 2003, Moghaddam and Javitt, 2012, Moghaddam and Krystal, 2012). Therefore, NMDAR antagonists provide an elegant pharmacological model of NMDAR-mediated abnormalities in schizophrenia. Given that dopaminergic antipsychotic medications do not improve neurocognitive or neurophysiological abnormalities in schizophrenia (Buchanan et al., 2007, Ford et al., 1994, Keefe et al., 2007, Umbricht et al., 1998, Umbricht et al., 1999), there is interest in identifying novel pharmacological targets with potential to improve these abnormalities, directly or via amelioration of NMDAR hypofunction. One possible target is nicotinic acetylcholine receptor (nAChR) augmentation, which has been shown to improve cognition (Newhouse et al., 2004, Rezvani and Levin, 2001, Swan and Lessov-Schlaggar, 2007) and associated neurophysiological measures (Polich and Criado, 2006, Pritchard et al., 2004). Accordingly, we examined whether pharmacological augmentation of nAChRs can attenuate the neurophysiological consequences of NMDAR hypofunction induced by ketamine. We focused on the mismatch negativity (MMN), an event-related potential (ERP) component that is reduced by schizophrenia (see Erickson et al., 2016) and NMDAR antagonists (see Rosburg and Kreitschmann-Andermahr, 2016).
MMN is an auditory ERP elicited by infrequent deviant sounds interspersed among frequent “standard” sounds. MMN has been considered to reflect auditory echoic memory (Näätänen et al., 2005, Näätänen and Kähkönen, 2009, Näätänen et al., 2004) and predictive coding in the auditory system (Friston, 2005, Garrido et al., 2009, Stephan et al., 2006, Stephan et al., 2009). Although MMN is elicited pre-attentively (Näätänen and Kähkönen, 2009), it correlates with higher-order cognition and functional outcomes in schizophrenia patients (Baldeweg et al., 2004, Hamilton et al., in press, Light and Braff, 2005, Wynn et al., 2010) and healthy individuals (Light et al., 2007).
MMN amplitude is reduced in schizophrenia (Erickson et al., 2016, Umbricht and Krljes, 2005). Moreover, NMDAR antagonists reduce MMN in animal (e.g., Ehrlichman et al., 2008, Javitt et al., 1996) and human (Gunduz-Bruce et al., 2012, Heekeren et al., 2008, Knott et al., 2012, Kreitschmann-Andermahr et al., 2001, Schmidt et al., 2013, Umbricht et al., 2000) studies. A recent meta-analysis showed ketamine to significantly reduce MMN amplitude in most human studies (Rosburg and Kreitschmann-Andermahr, 2016), despite some failures to demonstrate these effects (Mathalon et al., 2014, Oranje et al., 2000, Roser et al., 2011). Conversely, some have shown nAChR agonists, principally nicotine, to enhance MMN amplitude in healthy individuals (Baldeweg et al., 2006, Dunbar et al., 2007, Harkrider and Hedrick, 2005, Martin et al., 2009), although others failed to demonstrate this enhancement (Inami et al., 2005, Inami et al., 2007, Knott et al., 2011, Martin et al., 2009, Mathalon et al., 2014). Some have shown enhancement of MMN by nAChR agonists only in subgroups of individuals with low MMN amplitudes at baseline (Impey et al., 2015, Knott et al., 2015, Knott et al., 2014, Smith et al., 2015). In schizophrenia, the effects of nicotine have also been mixed (see Dulude et al., 2010, Fisher et al., 2012, Inami et al., 2007). Mixed results may partly depend on the type of deviance used to elicit MMN in specific studies, arguing for use of multi-deviant paradigms within a single study (Näätänen et al., 2004).
Several mechanisms may explain potential nAChR agonist enhancement of neurocognitive and neurophysiological function. Nicotinic agonists facilitate glutamatergic neurotransmission in rat prefrontal cortex (Gioanni et al., 1999, Lambe et al., 2003) and hippocampus (Radcliffe et al., 1999), possibly via presynaptic nAChRs (McGehee et al., 1995) or GABA interneurons (Alkondon et al., 1999, Ji and Dani, 2000). Importantly, nicotine has been shown to attenuate or reverse NMDAR antagonist-induced memory and attentional deficits in rats (Levin et al., 1998, Rezvani and Levin, 2003), whereas NMDAR antagonists can block nicotinic enhancement of memory consolidation in mice (Ciamei et al., 2001). In a study examining the interaction of ketamine and nicotine in healthy humans, ketamine reduced frequency deviant MMN, but co-administration of nicotine blocked this effect in a subgroup prone to sub-threshold delusional/hallucinatory experiences (Knott et al., 2012). Previously, we failed to replicate these effects on duration deviant MMN (Mathalon et al., 2014), although we may have lacked sufficient power given the study's small sample size.
Accordingly, the present placebo-controlled study examined the interactive effects of ketamine and nicotine on MMN in a relatively large sample of healthy volunteers. We hypothesized that 1) ketamine alone would reduce MMN amplitude, 2) nicotine alone would increase MMN amplitude, and 3) nicotine combined with ketamine would attenuate ketamine's disruptive effects on MMN. Given inconsistent effects of ketamine and nicotine on MMN as a function of the type of auditory deviance used, we implemented a multi-deviant paradigm to simultaneously examine drug effects on intensity, frequency, duration, and frequency + duration double deviant MMN.
Because we used the identical paradigm in a previous study documenting MMN amplitude deficits in 24 early illness schizophrenia patients relative to healthy controls (Hay et al., 2015), we conducted a secondary analysis comparing the z-score profile of ketamine effects (relative to placebo norms) in the current sample with the z-score profile of schizophrenia effects (relative to healthy control norms) across MMN deviant types.
Section snippets
Ketamine-nicotine study participants
Participants were 30 healthy individuals (see Table 1) representing a subgroup from a previous report of ketamine-nicotine effects on neurocognitive measures (for full description of inclusion/exclusion criteria, see D'Souza et al. (2012)). Participants had no personal lifetime or family history of a major Axis I disorder based on structured interview (First et al., 2002) and were medically healthy based on physical exam and clinical laboratory testing. Participants were instructed to refrain
Effects of ketamine and nicotine on MMN
Grand average ERP waveforms and scalp topography maps are presented in Fig. 1. MMN amplitude means are presented in Fig. 2. MMN amplitudes appear attenuated (i.e., less negative) during ketamine compared to saline, whereas during nicotine, MMN appears enhanced (i.e., more negative) compared to saline. During ketamine + nicotine, MMN generally appeared attenuated relative to saline but comparable to ketamine alone.
Results of the mixed effects model are presented in Table 2. There was a main effect
Discussion
The present study investigated the effects of intravenous nicotine, an nAChR agonist, on reductions in MMN induced by ketamine, an NMDAR antagonist, in a relatively large sample of healthy volunteers. Given inconsistencies in ketamine and nicotine effects on MMN in the prior literature, our use of a multi-deviant paradigm allowed us to investigate differential drug effects on various dimensions of auditory deviance simultaneously in the same sample. As expected, ketamine produced a reduction in
Role of funding source
This study was supported by a grant from AstraZeneca to Deepak C. D'Souza, and National Institute of Mental Health Grants R01 MH076989 and MH058262, and T32 MH089920. AstraZeneca and NIMH had no further role in the study design; in the collection, analysis, and interpretation, of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Drs. Mathalon, D'Souza, and Ford and Mr. Roach were responsible for the design of the study and the supervision of data collection. Dr. Hamilton took the lead on writing the manuscript in consultation with all authors. All authors contributed to and approved the final manuscript.
Conflicts of interest
Deepak C. D'Souza has in the past 3 years received or currently receives research grant support administered through Yale University School of Medicine from AstraZeneca, Abbott Laboratories, Eli Lilly Inc., Organon, Pfizer Inc., and Sanofi; he is a consultant for Bristol Meyers-Squibb. Mohini Ranganathan has received in the past 3 years or currently receives research grant support administered through Yale University School of Medicine from Insys Therapeutics and Pfizer Inc. Daniel H. Mathalon
Acknowledgments
This study was supported by AstraZeneca, the U.S. Department of Veterans Affairs and the Yale Center for Clinical Investigation. Holly K. Hamilton is supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment and the Sierra-Pacific Mental Illness Research, Education, and Clinical Center. We also thank Angelina Genovese, R.N.C., M.B.A.; Elizabeth O′Donnell, R.N.; Sonah Yoo, R.Ph.; Rachel Galvan, R.Ph.; and
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