Nicotine Effects on Mismatch Negativity in ...

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 [email protected] www.karger.com

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

Nicotine and MMN in Schizophrenia

Neuropsychobiology 2007;56:64–72

65

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.

66


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).



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).

67

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.

68



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.



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.

69

References 1 Levin ED, Simon BB: Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology (Berl) 1998; 138: 217–230. 2 Rezvani AH, Levin ED: Cognitive effects of nicotine. Biol Psychiatry 2001; 49:258–267. 3 Picciotto MR, Caldarone BJ, King SL, Zachariou V: Nicotinic receptors in the brain: links between molecular biology and behavior. Neuropsychopharmacology 2000; 22: 451– 465. 4 White HK, Levin ED: Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment. Psychopharmacology (Berl) 2004; 171:465–471. 5 Sjoberg R, Svensson AL, Zhang X, Nordberg A: Neuronal nicotinic receptor activation: a promising strategy for the treatment of Alzheimer’s disease. Int J Geriatr Psychopharmacol 1998;108:695–703. 6 Davies P, Maloney AJ: Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 1976;2:1403. 7 Kelton MC, Kahn HJ, Conrath CL, Newhouse PA: The effects of nicotine on Parkinson’s disease. Brain Cogn 2000;43:274–282. 8 Levin ED, Conners CK, Silva D, Canu W, March J: Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder. Exp Clin Psychopharmacol 2001;9:83–90. 9 Tanabe J, Tregellas JR, Martin LF, Freedman R: Effects of nicotine on hippocampal and cingulate activity during smooth pursuit eye movement in schizophrenia. Biol Psychiatry 2006;59:754–761. 10 Sacco KA, Termine A, Seyal A, Dudas MM, Vessicchio JC, Krishnan-Sarin S, Jatlow PI, Wexler BE, George TP: Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry 2005;62:649–659. 11 Kumari V, Postma P: Nicotine use in schizophrenia: the self-medication hypotheses. Neurosci Biobehav Rev 2005;29:1021–1034. 12 Potter D, Summerfelt A, Gold J, Buchanan RW: Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia. Schizophr Bull 2006;32:692– 700. 13 Smith RC, Warner-Cohen J, Matute M, Butler E, Kelly E, Vaidhyanathaswamy S, Khan A: Effects of nicotine nasal spray on cognitive function in schizophrenia. Neuropsychopharmacology 2006;31:637–643. 14 Mexal S, Frank M, Berger R, Adams CE, Ross RG, Freedman R, Leonard S: Differential modulation of gene expression in the NMDA postsynaptic density of schizophrenic and control smokers. Brain Res Mol Brain Res 2005;139:317–332.

70

15 Imperato A, Mulas A, Di Chiara G: Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats. Eur J Pharmacol 1986;132:337–338. 16 Lambe EK, Picciotto MR, Aghajanian GK: Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex. Neuropsychopharmacology 2003; 28: 216–225. 17 Vidal C: Nicotinic receptors in the brain: molecular biology, function, and therapeutics. Mol Chem Neuropathol 1996;28:3–11. 18 Toth E, Sershen H, Hashim A, Vizi ES, Lajtha A: Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid. Neurochem Res 1992;17:265–271. 19 Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS: Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994;51:199–214. 20 Tsai G, Passani LA, Slusher BS, Carter R, Baer L, Kleinman JE, Coyle JT: Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Arch Gen Psychiatry 1995;52:829–836. 21 Javitt DC, Zukin SR: Recent advances in the phencyclidine model of schizophrenia (see comments). Am J Psychiatry 1991;148:1301– 1308. 22 Krystal JH, Belger A, Abi-Saab W, Moghaddam B, Charney DS, Anand A, Madonick S, D’Souza C: Glutamatergic contributions to cognitive dysfunction in schizophrenia; in Sharma T, Harvey P (eds): Cognition in Schizophrenia. New York, Oxford University Press Inc, 2000, pp 126–153. 23 Houlihan ME, Pritchard WS, Robinson JH: Faster P300 latency after smoking in visual but not auditory oddball tasks. Psychopharmacology (Berl) 1996;123:231–238. 24 Edwards JA, Wesnes K, Warburton DM, Gale A: Evidence of more rapid stimulus evaluation following cigarette smoking. Addict Behav 1985;10:113–126. 25 Houlihan ME, Pritchard WS, Robinson JH: Effects of smoking/nicotine on performance and event-related potentials during a shortterm memory scanning task. Psychopharmacology (Berl) 2001;156:388–396. 26 Näätänen R: The role of attention in auditory information processing as revealed by eventrelated potentials and other brain measures of cognitive function. Beh Brain Sci 1990;13: 201–288. 27 Näätänen R: Attention and Brain Function. Hillsdale, Erlbaum, 1992. 28 Näätänen R, Paavilainen P, Tiitinen H, Jiang D, Alho K: Attention and mismatch negativity. Psychophysiology 1993; 30:436–450.


29 Näätänen R, Jiang D, Lavikainen J, Reinikainen K, Paavilainen P: Event-related potentials reveal a memory trace for temporal features. Neuroreport 1993;5:310–312. 30 Näätänen R, Alho K: Mismatch negativity – a unique measure of sensory processing in audition. Int J Neurosci 1995;80:317–337. 31 Näätänen R, Alho K: Mismatch negativity to change in complex spectrotemporal sound pattern: a new way to study neural learning in the human brain. Electroencephalogr Clin Neurophysiol Suppl 1995; 44:179–184. 32 Javitt DC, Doneshka P, Grochowski S, Ritter W: Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia. Arch Gen Psychiatry 1995;52:550–558. 33 Alho K, Woods DL, Algazi A, Knight RT, Näätänen R: Lesions of frontal cortex diminish the auditory mismatch negativity. Electroencephalogr Clin Neurophysiol 1994; 91: 353–362. 34 Giard MH, Perrin F, Pernier J, Bouchet P: Brain generators implicated in the processing of auditory stimulus deviance: a topographic event-related potential study. Psychophysiology 1990; 27:627–640. 35 Cowan N, Winkler I, Teder W, Näätänen R: Memory prerequisites of mismatch negativity in the auditory event-related potential (ERP). J Exp Psychol Learn Mem Cogn 1993; 19:909–921. 36 Javitt DC, Grochowski S, Shelley AM, Ritter W: Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance, probability, and interstimulus/interdeviant interval. Electroencephalogr Clin Neurophysiol 1998;108:143– 153. 37 Ritter W, Sussman E, Molholm S, Foxe JJ: Memory reactivation or reinstatement and the mismatch negativity. Psychophysiology 2002;39:158–165. 38 Schroger E: On the detection of auditory deviations: a pre-attentive activation model. Psychophysiology 1997; 34:245–257. 39 Yabe H, Tervaniemi M, Reinikainen K, Näätänen R: Temporal window of integration revealed by MMN to sound omission. Neuroreport 1997;8:1971–1974. 40 Adler LE, Hoffer LD, Wiser A, Freedman R: Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 1993;150:1856–1861. 41 Dalack GW, Meador-Woodruff JH: Smoking, smoking withdrawal and schizophrenia: case reports and a review of the literature. Schizophr Res 1996;22:133–141. 42 Goff DC, Henderson DC, Amico E: Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry 1992;149:1189–1194.


43 Anfang MK, Pope HG Jr: Treatment of neuroleptic-induced akathisia with nicotine patches. Psychopharmacology (Berl) 1997; 134:153–156. 44 Yang YK, Nelson L, Kamaraju L, Wilson W, McEvoy JP: Nicotine decreases bradykinesia-rigidity in haloperidol-treated patients with schizophrenia. Neuropsychopharmacology 2002; 27:684–686. 45 Glassman AH, Covey LS, Dalack GW, Stetner F, Rivelli SK, Fleiss J, Cooper TB: Smoking cessation, clonidine, and vulnerability to nicotine among dependent smokers. Clin Pharmacol Ther 1993;54:670–679. 46 Glassman AH: Cigarette smoking: implications for psychiatric illness. Am J Psychiatry 1993;150:546–553. 47 Lohr JB, Flynn K: Smoking and schizophrenia. Schizophr Res 1992;8:93–102. 48 Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC: Role of cortical N-methyl-D -aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia. Proc Natl Acad Sci USA 1996;93:11962–11967. 49 Javitt DC, Schroeder CE, Steinschneider M, Arezzo JC, Ritter W, Vaughan HG, Jr: Cognitive event-related potentials in human and non-human primates: implications for the PCP/NMDA model of schizophrenia. Electroencephalogr Clin Neurophysiol Suppl 1995;44:161–175. 50 Javitt DC, Doneshka P, Zylberman I, Ritter W, Vaughan HG Jr: Impairment of early cortical processing in schizophrenia: an eventrelated potential confirmation study. Biol Psychiatry 1993;33:513–519. 51 Shelley AM, Ward PB, Catts SV, Michie PT, Andrews S, McConaghy N: Mismatch negativity: an index of a preattentive processing deficit in schizophrenia. Biol Psychiatry 1991;30:1059–1062. 52 Inami R, Kirino E, Inoue R, Arai H: Transdermal nicotine administration enhances automatic auditory processing reflected by mismatch negativity. Pharmacol Biochem Behav 2005;80:453–461. 53 Engeland C, Mahoney C, Mohr E, Ilivitsky V, Knott VJ: Acute nicotine effects on auditory sensory memory in tacrine-treated and nontreated patients with Alzheimer’s disease: an event-related potential study. Pharmacol Biochem Behav 2002; 72: 457–464. 54 Knott V, Bosman M, Mahoney C, Ilivitsky V, Quirt K: Transdermal nicotine: single dose effects on mood, EEG, performance, and event-related potentials. Pharmacol Biochem Behav 1999;63:253–261. 55 Kumari V, Gray JA, Ffytche DH, Mitterschiffthaler MT, Das M, Zachariah E, Vythelingum GN, Williams SC, Simmons A, Sharma T: Cognitive effects of nicotine in humans: an fMRI study. Neuroimage 2003; 19:1002–1013.


56 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4 (rev). Washington, American Psychiatric Association, 1994. 57 Kay SR, Fiszbein A, Opler LA: The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261– 276. 58 Novak GP, Ritter W, Vaughan HG Jr, Wiznitzer ML: Differentiation of negative eventrelated potentials in an auditory discrimination task. Electroencephalogr Clin Neurophysiol 1990;75:255–275. 59 Kathmann N, Wagner M, Rendtorff N, Engel RR: Delayed peak latency of the mismatch negativity in schizophrenics and alcoholics. Biol Psychiatry 1995; 37:754–757. 60 O’Donnell BF, Shenton ME, McCarley RW, Faux SF, Smith RS, Salisbury DF, Nestor PG, Pollak SD, Kikinis R, Jolesz FA: The auditory N2 component in schizophrenia: relationship to MRI temporal lobe gray matter and to other ERP abnormalities. Biol Psychiatry 1993;34:26–40. 61 Salisbury DF, Farrell DC, Shenton ME, Fischer IA, Zarate C, McCarley RW: Mismatch negativity is reduced in chronic but not first episode schizophrenia (abstract). Biol Psychiatry 1999; 45(suppl):25s. 62 Salisbury DF, Shenton ME, Griggs CB, Bonner-Jackson A, McCarley RW: Mismatch negativity in chronic schizophrenia and first-episode schizophrenia. Arch Gen Psychiatry 2002;59:686–694. 63 Umbricht D, Javitt D, Bates J, Pollack S, Lieberman J, Kane J: Auditory event-related potentials (ERP) in first episode and chronic schizophrenia (abstract). Biol Psychiatry 1997;41(suppl):46s. 64 Salisbury DF, Shenton ME, Sherwood AR, Fischer IA, Yurgelun-Todd DA, Tohen M, McCarley RW: First-episode schizophrenic psychosis differs from first-episode affective psychosis and controls in P300 amplitude over left temporal lobe. Arch Gen Psychiatry 1998;55:173–180. 65 Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S: Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 2000;23:351–364. 66 Court J, Spurden D, Lloyd S, McKeith I, Ballard C, Cairns N, Kerwin R, Perry R, Perry E: Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alphabungarotoxin and nicotine binding in the thalamus. J Neurochem 1999;73:1590–1597. 67 Freedman R, Hall M, Adler LE, Leonard S: Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 1995;38:22–33.

68 Guan ZZ, Zhang X, Blennow K, Nordberg A: Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. Neuroreport 1999; 10: 1779–1782. 69 Carlsson A, Waters N, Carlsson ML: Neurotransmitter interactions in schizophrenia – therapeutic implications. Biol Psychiatry 1999;46:1388–1395. 70 Guo JZ, Tredway TL, Chiappinelli VA: Glutamate and GABA release are enhanced by different subtypes of presynaptic nicotinic receptors in the lateral geniculate nucleus. J Neurosci 1998;18:1963–1969. 71 Wonnacott S: Presynaptic nicotinic ACh receptors. Trends Neurosci 1997;20:92–98. 72 Wonnacott S, Kaiser S, Mogg A, Soliakov L, Jones IW: Presynaptic nicotinic receptors modulating dopamine release in the rat striatum. Eur J Pharmacol 2000;393:51–58. 73 Leonard S, Breese C, Adams C, Benhammou K, Gault J, Stevens K, Lee M, Adler L, Olincy A, Ross R, Freedman R: Smoking and schizophrenia: abnormal nicotinic receptor expression. Eur J Pharmacol 2000; 393: 237– 242. 74 Leonard S, Gault J, Adams C, Breese CR, Rollins Y, Adler LE, Olincy A, Freedman R, Leonard S, Breese C, Adams C, Benhammou K, Gault J, Stevens K, Lee M, Adler L, Olincy A, Ross R, Freedman R: Nicotinic receptors, smoking and schizophrenia: abnormal nicotinic receptor expression. Restor Neurol Neurosci 1998;12:195–201. 75 Court JA, Lloyd S, Thomas N, Piggott MA, Marshall EF, Morris CM, Lamb H, Perry RH, Johnson M, Perry EK: Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use. Neuroscience 1998; 87:63–78. 76 Adler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R: Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia: comparison of medicated and drug-free patients. Biol Psychiatry 1982; 17:639–654. 77 Freedman R, Adler LE, Waldo MC, Pachtman E, Franks RD: Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: comparison of medicated and drug-free patients. Biol Psychiatry 1983; 18:537–551. 78 Freedman R, Leonard S, Gault JM, Hopkins J, Cloninger CR, Kaufmann CA, Tsuang MT, Farone SV, Malaspina D, Svrakic DM, Sanders A, Gejman P: Linkage disequilibrium for schizophrenia at the chromosome 15q13–14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am J Med Genet 2001;105:20–22.


71

79 Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W: Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 1997; 94: 587–592. 80 Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins AC, Leonard S: Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 1997;282:7–13.

72

81 Leonard S, Adams C, Breese CR, Adler LE, Bickford P, Byerley W, Coon H, Griffith JM, Miller C, Myles-Worsley M, Nagamoto HT, Rollins Y, Stevens KE, Waldo M, Freedman R: Nicotinic receptor function in schizophrenia. Schizophr Bull 1996;22:431–445. 82 Ereshefsky L, Jann MW, Saklad SR, Davis CM, Richards AL, Burch NR, Jann MW, Saklad SR, Ereshefsky L, Richards AL, Harrington CA, Davis CM: Effects of smoking on fluphenazine clearance in psychiatric inpatients. Biol Psychiatry 1985; 20:329–332.


83 Jann MW, Saklad SR, Ereshefsky L, Richards AL, Harrington CA, Davis CM: Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance. Psychopharmacology (Berl) 1986;90:468–470. 84 McEvoy JP, Freudenreich O, Levin ED, Rose JE: Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology (Berl) 1995;119:124–126. 85 McEvoy J, Freudenreich O, McGee M, VanderZwaag C, Levin E, Rose J: Clozapine decreases smoking in patients with chronic schizophrenia. Biol Psychiatry 1995;37:550– 552.
