Original Paper Neuropsychobiology 2007;56:64–72 DOI: 10.1159/000111536
Received: January 12, 2007 Accepted after revision: September 13, 2007 Published online: November 23, 2007
Nicotine Effects on Mismatch Negativity in Nonsmoking Schizophrenic Patients Rie Inami a Eiji Kirino a, b Reiichi Inoue b Toshihito Suzuki a, b Heii Arai a, b a
Department of Psychiatry, Juntendo University School of Medicine, and b Juntendo Institute of Mental Health, Koshigaya, Japan
Key Words Nicotine Mismatch negativity Schizophrenia
Abstract Background: The goal of the present study is to identify the effect of nicotine on auditory automatic processing, as reflected by mismatch negativity (MMN), in nonsmoking schizophrenic patients. Methods: Ten nonsmoking schizophrenic patients and 10 healthy volunteers underwent a reference session and 2 test sessions. The test sessions involved administration of a placebo patch and a nicotine skin patch, which were counterbalanced. Nicotine was administered transdermally under controlled dosage. Results: Nicotine administration shortened the MMN latencies (at Fz on nicotine/placebo: 134.8 8 5.7/157.6 8 6.4 ms) in healthy volunteers. In contrast, there were no significant differences in MMN latencies in schizophrenic patients (169.6 8 5.7/165.0 8 6.4 ms). Conclusion: Nicotine activates and accelerates preattentive and automatic processing in healthy controls, whereas there were no such effects observed in nonsmoking patients. The impaired MMN response to nicotine administration in nonsmoking schizophrenic patients may be attributed to low nicotinic receptor function, implicated in dysregulation of the glutamatergic system. Copyright © 2007 S. Karger AG, Basel
These findings were presented at the 2006 International PharmacoEEG Society Symposium and we were encouraged by the society to submit our manuscript to Neuropsychobiology
© 2007 S. Karger AG, Basel 0302–282X/07/0563–0064$23.50/0 Fax +41 61 306 12 34 E-Mail
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Accessible online at: www.karger.com/nps
Introduction
Nicotine acts on the cholinergic system as an agonist at 1 of the 2 principal classes of receptor for the endogenous transmitter, acetylcholine [1, 2]. Nicotine interacts with the presynaptic nicotinic acetylcholine receptor and facilitates the release of neurotransmitters, including dopamine, noradrenalin (NA), serotonin (5-HT), -aminobutyric acid and glutamate [3]. Nicotine has cognitiveenhancing effects, and due to its selective activation of remaining central nicotinic acetylcholine receptors, it is considered a promising treatment for age-associated memory impairment [4], Alzheimer’s disease [5, 6], Parkinson’s disease [7], attention deficit hyperactive disorder [8] and schizophrenia [9–14]. Nicotine modulates the activity of midbrain dopamine neurons as well as cortical glutamatergic inputs to the ascending dopamine systems [15, 16]. Stimulation of presynaptic nicotinic receptors on glutamatergic neurons increases the extracellular levels of glutamate in the prefrontal cortex [17] and enhances the excitatory glutamatergic inputs to the midbrain dopamine tracts [18]. Deficits in N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission may contribute to the clinical pathophysiology of schizophrenia [19–22]. Several reports have evaluated the effects of nicotine on cognitive function by studying event-related potentials (ERPs). P300 amplitudes are one of the most frequently reported components of ERPs and are especially sensitive to nicotine levels [23]. There is evidence that nicEiji Kirino Juntendo University Shizuoka Hospital 1129 Nagaoka Izunokunishi Shizuoka 4102211 (Japan) Tel. +81 55 948 3111, Fax +81 55 948 5088, E-Mail
[email protected]
otine decreases P300 latency in visual but not auditory tasks [23, 24], although there are conflicting data on this. Although the effect of smoking on N200 was small relative to its effects on reaction time, smoking decreased N200 latency for the memory set stimuli and negative probes during a short-term memory-scanning task [25]. Another component of ERPs is mismatch negativity (MMN). MMN is generated by a neuronal mismatch process between the sensory memory input from a deviant auditory stimulus (deviant) and a memory trace of frequent auditory stimuli (standard). The MMN is elicited even when the subjects are instructed to ignore the stimulation of the auditory channel, therefore it has been suggested that the MMN is generated by an automatic process [26–31]. Javitt et al. [32] hypothesized that MMN should be considered an index of an automatic alerting mechanism designed to stimulate individuals to explore unexpected environmental events. MMN has a frontocentral scalp distribution pattern that can be modeled with generator sources in anterior regions of the supratemporal auditory cortex. An additional MMN generator in the frontal cortex has been identified, indicating that frontotemporal projections or frontotemporal feedback processes may play a critical role in efficient MMN generation [30, 33, 34]. The deviant is not compared to the representations of individual tones but rather to the representations of invariance across tones (regularities in features or relationships between tones) [35–38]. During the tone pips, which intervene in regular silent intervals, occasionally the shorter intervals, but not the longer, can elicit MMN. On the other hand, clear MMN was elicited by stimulus omission in a sequence of regularly spaced tone pips [39]. These reports indicate that MMN generation seems to be due to something more than just new afferent elements activated by deviant but nonstandard stimuli [29]. There is a transient but significant improvement in auditory sensory gating after nicotine administration in schizophrenic patients [40]. In both schizophrenic and control groups of smokers, overnight abstinence reduced the Continuous Performance Test hit rate, while visuospatial working memory was impaired only in smokers with schizophrenia. Smoking reinstatement reversed the abstinence-induced cognitive impairment [10]. These findings have led to the speculation that the prevalence of smoking among schizophrenics, which is nearly 3 times higher than that of the general population, is because nicotine partially remediates attentional and sensory processing deficits [41]. Smoking may also reduce the unpleasant side effects of neuroleptic
medications, specifically Parkinson’s symptoms or akathisia, by stimulating dopamine release [42–44]. Smoking in schizophrenia may represent self-medication to restore a deregulated corticomesolymbic system [11, 45–47]. NMDA receptors may be critically involved in MMN generation [48, 49]. Intracortical recordings and pharmacological micromanipulations in awake monkeys have demonstrated that both competitive and noncompetitive NMDA antagonists block the generation of MMN without affecting prior obligatory activity in the primary auditory cortex [48]. Javitt et al. [32, 36, 50] and Shelley et al. [51] reported attenuated MMN in schizophrenic patients and hypothesized that the memory impairment underlying the MMN might be related to the impaired working memory observed in schizophrenic patients. NMDA deficits seen in schizophrenic patients may be related to their impaired MMN. In our preliminary report [52], in which nicotine was administered transdermally under a controlled dosage regimen, the MMN latencies were shortened after nicotine administration in healthy non-smoking adults. These effects on MMN were independent of ERP components, such as N100 and P200, reflecting an earlier stage than preattentive mismatch processing. The findings indicated that nicotine enhanced preattentive and automatic processing, such as the MMN system, and that these effects appeared to be specific and independent of earlier cognitive stages. The shortened MMN latency could be interpreted as a reduction in the amount of time required to complete a neuronal mismatch process through the ascending auditory pathway. Engeland et al. [53] recorded the MMN in Alzheimer’s disease patients receiving tacrine treatment, and those receiving no treatment, during pre- and post- oral nicotine administration. MMN amplitudes increased with nicotine administration in non-treated, but not tacrinetreated patients, and the MMN latencies were shortened by nicotine in both treatment groups. The control of nicotine dosage is complex and must be carefully regulated by considering smoking behavior, negative effects of abstinence and many other individual differences. Although previous reports examining cognition have generally agreed that smoking can improve performance on a variety of tasks, these cognitive potentials have not always responded to acute smoking or have responded in a less than robust fashion. Despite this inconsistency, there is general agreement that identification of the effects of smoking/nicotine requires the use of
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a nicotine delivery system other than smoking to control dosage more effectively. Transdermal administration of nicotine produces a nicotine-blood level pattern distinct from other delivery methods, such as smoking, chewing or subcutaneous administration. Transdermal nicotine administration delivers a systemic dose over a 24-hour period [25, 53–55]. Nicotine and MMN are implicated as neural substrates of cognitive dysfunction in schizophrenia. The goal of the present study is to identify the effects of nicotine on auditory automatic processing in nonsmoking schizophrenic patients.
Methods and Materials Subjects Ten right-handed, nonsmoking schizophrenic patients (5 males, 5 females) between the ages of 19 and 37 years (27.7 8 6.7) and 10 age-, handedness- and gender-matched nonsmoking healthy volunteers (5 males, 5 females) between the ages of 26 and 39 years (30.0 8 5.1) were recruited. Nine patients and 8 healthy controls had never had a smoking habit, which was defined as regularly smoking more than 1 cigarette per week. The 3 participants who had formally smoked had abstained from smoking for over a year. The participants were asked to abstain from coffee, alcohol and drugs, except for the medications administered to patients prior to testing. The DSM-IV [56] diagnosis and the Positive And Negative Syndrome Scale [57] were ascertained on the basis of a structured psychiatric interview and a review of patients’ medical charts. The patients’ duration of illness was 4 months to 16 years (11.9 8 1.7 years). Their Positive And Negative Syndrome Scale scores were 15.5 8 3.0 (positive scales), 19.8 8 4.6 (negative scales), 36.3 8 10.1 (general scales) and 70.7 8 14.4 (total score). All of the patients were hospitalized at the time of testing and were receiving pharmacological treatments. The patient population was selected on the condition that they were able to cooperatively participate in the study tests, therefore these subjects had relatively mild psychotic manifestations. Their dosage of antipsychotics equivalent to risperidone was 4.3–22.5 mg (11.9 8 2.2). Four patients were on a typical antipsychotic, 4 were on serotonin dopamine antagonist (SDA) in conjunction with a typical antipsychotic, 1 was on SDA alone and 1 was on SDA in conjunction with multiactive receptor targeted agent. The patients’ medications were not changed during the 3-day course of the study. All patients were judged to be in good physical health on the basis of medical history, physical examination and laboratory measures. None of the subjects had a history of electroconvulsive shock treatment, alcohol or other drug abuse (DSM-IV criteria), addiction or a neurological illness affecting the central nervous system. All subjects reported that they had normal hearing. After a complete description of the study had been presented to the subjects, they all gave informed consent for this protocol, which was approved by the Institutional Review Board of the Juntendo Institute of Mental Health.
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Study Design The subjects underwent 1 reference session and 2 test sessions. Study measurements were performed at the same time of day on 3 consecutive days. The first day was the reference point, with administration of neither placebo nor nicotine. The 2nd and 3rd days were test sessions, with ERP recordings taken in the evening, 8 h after nicotine or placebo administration via the skin patch application. The test sessions involved administration of a placebo patch and a nicotine skin patch, which were counterbalanced. Nicotine Administration Nicotine was administered by a transdermal nicotine skin patch (Nicotinell TTS 20) that delivers a systemic dose of 16.1 8 2.7 mg/day over 24 h (AUC0–36: 474.9 8 86.7 ng h/ml). Nicotinell TTS covers 20 cm2 and has a total nicotine content of 35 mg. A maximum plasma nicotine concentration of 21.9 8 3.0 ng/ml is reached 9 h after a single application. The placebo patch was similar in size and color, and both the active and placebo patches were applied to an area on the upper back of the subjects. None of the subjects were able to distinguish between the active and placebo patches upon questioning at the end of the 2 test sessions. Experimental Tasks and Procedure The ERPs were recorded during an auditory oddball paradigm. A computer with custom-designed software generated acoustic stimuli and controlled both stimulus timing and presentation. Tones were presented binaurally at a constant listening level (75 dB sound pressure level) through electrically shielded headphones held in place by a headset. The acoustic stimuli consisted of tones (sine waves) with a duration of 80 ms, including 10 ms rise and fall times. The frequency of the standard tones (probability = 0.95) and the deviant tones (probability = 0.05) were 1,000 and 1,050 Hz, respectively, and the onset-to-onset interval was 600 ms. The experimental task consisted of a single block, which included 2,000 tones. For each subject, an ERP session on 1 condition took about 20 min. ERP Recording and Analysis ERPs were recorded in an entirely ‘passive’ condition, in which the subjects were asked to ignore the stimuli and watch a silent movie projected on a video monitor. To standardize their level of attention, all subjects were told that they would have to give specific feedback about the movie at the end of the ERP session. They were instructed to avoid unnecessary eye movement and eye blinking during the session. ERPs were recorded from Ag/AgCl disk electrodes placed at 13 scalp sites (F3, Fz, F4, C3, Cz, C4, P3, Pz, P4, O1, O2, T5, T6) of the standard 10/20 system and recording electrodes were referenced to the nose. Additional electrodes were placed at the left and right mastoids under the ears. A bipolar electrode pair was placed above and over the outer canthus of the right eye to record the electro-oculogram (EOG). The impedances of all electrodes were maintained below 5 k. EEG data were recorded and analyzed using the Brain Atlas 2 (Bio-Logic) system. During the task, the EEG and EOG were continuously digitized at 500 Hz per channel and stored on a computer disk using a 0.1- to 100-Hz on-line filter. EEG was filtered off-line with a bandpass of 0.1–35 Hz. At the conclusion of the experiment, EEG epochs of 512 ms duration (100 ms before
Inami /Kirino /Inoue /Suzuki /Arai
Difference waveform (deviant – standard)
MMN Deviant
detected within the latency ranges of 120–185 ms. For the purpose of this study, analyses were restricted to MMN amplitudes at Fz and Cz and latencies at Fz. The MMN amplitudes were calculated for each subject as the mean amplitude in a 50-ms time window centered on each subject’s peak latency and then tabulated for the next procedure. The MMN amplitudes were measured relative to the prestimulus baseline.
N100 P200 Standard N100 P200
a Difference waveform (deviant – standard)
Deviant
MMN
N100 Standard N100
1μV
b
100 ms
P200 Baseline Placebo Nicotine
Statistical Analysis The MMN data were analyzed by analysis of variance (ANOVA) with repeated measures. For MMN amplitudes at Fz and Cz, ANOVAs with 2 repeated measures were performed. There were 3 factors, group (patients, controls) as a between-subject factor, and drug (reference point, placebo, nicotine) and electrode (Fz, Cz) as within-subject factors. For MMN latencies at Fz, group and drug were used as factors. Reduced degrees of freedom (Greenhouse-Geisser) were used when appropriate to counter violations of the sphericity assumption underlying ANOVA with repeated measures (-values were provided). values of 0.05 were considered significant. For intragroup comparisons, Dunnett’s post hoc procedures were carried out for MMN latencies at Fz. All statistics were performed using SPSS for Windows (SPSS, Chicago, Ill., USA).
Results
and 412 ms after stimulus) associated with each stimulus type were excised from the continuous record. The root mean square voltage of the EOG channel was computed to identify and discard epochs associated with eye movements and blink artifacts. The thresholds of automatic trial rejection were +/– 80 V. Off-line visual inspection of data blind to patient or control eliminated epochs contaminated by EOGs, blinks or muscle artifacts exceeding an artifact rejection threshold of +/– 80 V at any electrode from the analysis. All single-trial epochs were prestimulus-baseline-corrected prior to the subsequent process. Artifact-free epochs were segregated by stimulus codes and averaged for each subject. There was no significant difference in the amount of accepted epochs between the conditions. A group average across all 10 subjects of each group was also computed. Difference waveforms were constructed by subtracting the waveform of the standards from that of the deviants. In every condition, topographic distributions were inspected to verify that the maximum MMN was observed at the Fz or Cz electrodes, where the MMN is usually the largest. Peak amplitudes of MMN were
All participants correctly answered the questionnaires about the movie at the end of the ERP session. Polarity reversal of MMN waveforms between the mastoids and other electrodes was observed in all subjects, which indicated that the component defined as MMN in the present experiments was confirmed as that previously defined by Novak et al. [58] (fig. 1). MMN latency ANOVA confirmed the effect of group [F(1, 18) = 5.542, p = 0.030] and the interaction of drug ! group [F(2, 36) = 3.309, p = 0.048]. The MMN latencies at Fz were 157.6 8 7.5 ms for the reference point, 157 8 6.4 ms for placebo and 134.8 8 5.7 ms for nicotine. Within the controls, using Dunnett’s post hoc procedures, the MMN latencies at Fz for nicotine were shorter than those for the reference point (p = 0.003) and placebo (p = 0.003). Within the patients, there were no significant differences in MMN latencies between the reference point (163.4 8 7.5 ms), placebo (165.0 8 6.4 ms) and nicotine (169.6 8 5.7 ms). In the nicotine condition, the MMN latencies of the controls were significantly shorter than those of the patients [Fz (p = 0.000), Cz (p = 0.006)]. The effects of drug [F(2, 36) = 2.206, p = 0.125] and electrode [F(1, 18) = 0.006, p = 0.938], and the interactions of drug ! electrode [F(2, 36) = 0.558, p = 0.577], electrode ! group [F(1, 18) = 0.001, p = 0.979] and drug ! electrode ! group [F(2, 18) = 0.783, p = 0.465] were not significant (tables 1, 2).
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Fig. 1. Grand averaged waveforms (Fz). Negative deflection with-
in the latency ranges of 120–185 ms was recognized as MMN. Polarity reversal of MMN waveforms between the mastoid and other electrodes was observed. Positive values appear above the baseline and negative values appear below. Group effect and drug ! group interaction in MMN latencies were significant. Although the differences are subtle, the MMN peaks of the controls (b), in particular in the nicotine condition, are earlier compared with those of the patients (a).
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MMN amplitude ANOVA revealed a significant effect of the electrode [F(1, 18) = 18.375, p ! 0.001] but not the drug [F(2, 36) = 0.885, p = 0.431] or the group [F(1,18) = 0.060, p = 0.809]. The interactions of drug ! electrode [F(2,36) = 1.038, p = 0.365], drug ! group [F(2,36) = 0.825, p = 0.446], group ! electrode [F(1,18) = 2.058, p = 0.169] and group ! drug ! electrode [F(2,36) = 1.763, p = 0.186] were not significant (tables 1, 2)
normal cognitive function of schizophrenic patients [10, 11]. However, there are reports of patients having different responses to nicotine than controls. Mexel et al. [14] reported differential modulation of gene expression in the NMDA postsynaptic density of schizophrenic patients and controls, suggesting that smoking might differentially modulate glutamatergic function. Tanabe et al. [9] reported that, in controls, nicotine gum administration reduced the activity in the hippocampus and anterior cingulated gyrus during smooth pursuit eye movement, as measured by functional MRI, representing an improvement in inhibitory function and attention. In schizophrenic patients, these effects were dampened in
Discussion
The present findings suggest that nicotine has different effects on MMN latencies between controls and schizophrenic patients. Nicotine activates and accelerates automatic processing, as reflected by MMN latencies, in healthy controls, while no such effects are observed in nonsmoking patients. We did not observe a significant difference in MMN amplitudes between controls and schizophrenic patients. This is in accord with certain negative studies [59, 60]. It has also been reported that MMN is not reduced in schizophrenic patients at their first hospitalization [61– 63]. Salisbury et al. [64] hypothesized that reductions in MMN amplitude might develop over time and may indicate the progression of the disorder. These reports correspond with the results of the present study, in which the patient population had relatively mild manifestations of psychotic symptoms and exhibited no reduction in mean MMN amplitude. As mentioned in the introduction, in addition to the cognitive-enhancing effects of nicotine in healthy controls, there have been several reports that nicotine administration or smoking transiently ameliorates the ab-
Table 1. Amplitude and latency of MMN (Fz, Cz) (mean 8 SD)
Patients Amplitudes, v Fz Cz Latencies, ms Fz Cz Controls Amplitudes, v Fz Cz Latencies, ms Fz Cz
Reference
Placebo
Nicotine
–2.9882.20 –2.3182.19
–2.6781.83 –2.6881.90
–1.7582.64 –1.1682.82
163.4826.2 165.6826.9
165.0819.7 166.8820.2
169.6821.6 165.4828.2
–2.6983.13 –2.0082.52
–3.0182.35 –2.1382.42
–2.9381.84 –1.9981.68
157.6820.7 157.0822.0
157.6820.6 157.6820.0
134.8813.8* 135.0813.0
* p < 0.05.
Table 2. Summary of the statistical analyses for MMN
Source (d.f.)
Drug (2, 36) Electrode (1, 18) Group (1, 18) Drug ! group (2, 36) Electrode ! group (1, 18) Drug ! electrode (1, 18) Drug ! electrode!group (1, 18)
Latency
Amplitude
F
p
F
p
– – 5.542 3.309 – – –
– – 0.030 0.048 – – –
– – – – – – –
– 18.375 – – – – –
– 0.000 – – – – –
– – – – – – –
The nonsignificant effects were omitted.
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Inami /Kirino /Inoue /Suzuki /Arai
the hippocampus or reversed in the anterior cingulated gyrus. Breese et al. [65] examined the effect of smoking history on the regulation of the high-affinity nicotinic receptor ligands, [3H]nicotine and [3H]epibatidine, and the low-affinity ligand [3H]methyllycaconitine in the postmortem brain of normal controls and schizophrenic subjects with varying smoking history. They concluded that, at the molecular level, schizophrenic smokers fail to upregulate their high-affinity nicotine receptors to the same degree as their healthy counterparts. Schizophrenic patients also express reduced levels of the low-affinity nicotine receptor 7 [66–68]. In schizophrenic patients with low nicotinic receptor levels, the responses of the neurotransmitter systems and other intracellular signaling pathways, triggered and modulated by nicotine and nicotinic receptors, may not be the same as in a subject with normal receptor function [14, 69–72]. Low levels of nicotinic receptors may have downstream consequences for several neurotransmitter systems implicated in both schizophrenia and nicotine dependence, including aminobutyric acid and glutamate [14, 73, 74]. It is not only the case for smoking schizophrenic patients, but also for nonsmoking schizophrenic patients, that differential regulation is due to low levels of nicotinic receptors, compared to nonsmoking controls [14]. Chronic smoking is associated with a reduction of dopamine turnover and increased numbers of high-affinity nicotine receptors, in the absence of changes in the numbers of dopamine receptors and the dopamine transporter. It is possible that the reduced dopamine turnover observed in smokers could be of symptomatic benefit to schizophrenic patients [75]. The differential effects of short-term nicotine administration, as in the present experimental design, on MMN latencies in nonsmoking schizophrenic patients may be attributed to their low nicotinic receptor function implicated in the dysregulation of the glutamatergic system [48, 49]. P50 sensory gating has been reported to be abnormal in schizophrenic patients, and nicotine can transiently reverse the P50 deficits seen in patients [40, 76, 77]. Both schizophrenia and P50 gating deficits have been linked to the 7-nicotinic cholinergic receptor subunit gene locus [67, 78, 79]. These receptors are critical to the inhibitory response and postmortem studies have revealed abnormal expression and regulation in brains of schizophrenic patients [65, 79, 80]. The modulatory effect of nicotine on P50 gating has been postulated to result from the increases in glutamate release following activation of the 7-nicotinic receptor subunit [11, 81]. Considering the relationship between abnormal function of glutamatergic neu-
rons and NMDA receptors and MMN generation and schizophrenia, the present findings of impaired MMN in response to nicotine administration might be implicated in the pathology reflected by P50 deficits in this disease. In order to identify the underlying pathophysiology implicated in MMN abnormality and nicotine receptor dysfunction in schizophrenia, further investigations are required employing long-term nicotine administration, or larger samples of both smoking controls and patients. Finally, we should address the limitations of the present study. A variety of medications including typical and atypical antipsychotics (SDA and multiactive receptor targeted agent) were administrated to the patients, which makes it difficult to evaluate and exclude their pharmacological effects on MMN under the nicotine exposure condition. Pharmacokinetic studies have shown that smoking generally increases the clearance of antipsychotic medications [82, 83]. On the other hand, haloperidol, a typical antipsychotic agent, leads to an increase in smoking as well as blood nicotine levels [84]. In contrast, clozapine, an atypical antipsychotic, is correlated with a decrease in smoking [85]. It was not possible in this report to determine the influence of antipsychotics on nicotine effects. Further investigations are required to answer these questions.
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Conclusion
Nicotine may have different effects on MMN latencies between healthy controls and schizophrenic patients. Nicotine activates and accelerates automatic processing, as reflected by MMN latencies, in healthy controls, while no such effects were observed in nonsmoking schizophrenic patients. The impaired MMN response to nicotine administration in nonsmoking schizophrenic patients may be attributed to low nicotinic receptor function, implicated in the dysregulation of the glutamatergic system.
Acknowledgments This work was supported by grants of the Research Support Foundation of the Juntendo Institute of Mental Health and Juntendo University Casualty Center, support activity of the Japan Keirin Association, and the Smoking Research Foundation.
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