Behavioral Neuroscience

Nicotine Normalizes Event Related Potentials inCOMT-Val-tg Mice and Increases Gamma and ThetaSpectral DensityYufei A. Cao, Robert E. Featherstone, Michael J. Gandal, Yuling Liang, Catherine Jutzeler, JohnSaunders, Valerie Tatard-Leitman, Jingshan Chen, Daniel R. Weinberger, Caryn Lerman, andSteven J. SiegelOnline First Publication, February 6, 2012. doi: 10.1037/a0027047

CITATIONCao, Y. A., Featherstone, R. E., Gandal, M. J., Liang, Y., Jutzeler, C., Saunders, J.,Tatard-Leitman, V., Chen, J., Weinberger, D. R., Lerman, C., & Siegel, S. J. (2012, February6). Nicotine Normalizes Event Related Potentials in COMT-Val-tg Mice and Increases Gammaand Theta Spectral Density. Behavioral Neuroscience. Advance online publication. doi:10.1037/a0027047

Nicotine Normalizes Event Related Potentials in COMT-Val-tg Mice andIncreases Gamma and Theta Spectral Density

Yufei A. Cao, Robert E. Featherstone,Michael J. Gandal, Yuling Liang, Catherine Jutzeler,

John Saunders, and Valerie Tatard-LeitmanUniversity of Pennsylvania

Jingshan Chen and Daniel R. WeinbergerNational Institute of Mental Health, Bethesda, Maryland

Caryn Lerman and Steven J. SiegelUniversity of Pennsylvania

Regulation of dopamine neurotransmission is essential for cognitive processes. In humans and rodents,the relationship between dopamine signaling and cognitive performance is described as a dose-dependent, inverted-U curve whereby excess or insufficiency of dopamine in prefrontal cortex hasdetrimental effects. Previous studies have indicated that prefrontal dopamine levels are associated withgenetic variation in catechol-O-methyltransferase (COMT), a regulatory enzyme that controls dopamineavailability. Furthermore, smokers who carry the high-activity COMT-Val allele are more prone tocognitive deficits and have an increased risk of smoking relapse. The present study employed transgenicmice expressing the human COMT-Val variant to determine the effects of the high-activity COMT alleleon electrophysiological markers, including the P20, N40, and P80 components of the auditory event-related potential, as well as baseline and auditory event-related power and phase-synchrony in theta andgamma ranges. We also examined the effects of nicotine on these measures to investigate the potentialeffects of smoking on COMT-mediated electrophysiological activity. COMT-Val-tg mice displayedincreased N40 latency and decreased P80 amplitude as well as reduced baseline theta and gamma power.Nicotine increased P20 and P80 amplitudes, decreased N40 amplitude, increased P20 and N40 latencies,and reduced P80 latency. Nicotine also increased the event-related power and phase synchrony, yieldingan increase in signal-to-noise ratio across theta and gamma ranges. COMT activity specifically alterslong-latency components of the event-related response. Nicotine restored normal event-related activityamong COMT-Val-tg mice, suggesting one mechanism through which nicotine may normalize cognitivefunction among people with the high-activity allele.

Keywords: catechol-O-methyltransferase, COMT, mouse, nicotine, event-related potential, EEG, gamma,theta

Proper regulation of dopamine neurotransmission is essential forcognitive processes such as attention, executive function, workingmemory, and learning. Disruptions of dopaminergic systems havebeen implicated in neuropsychiatric disorders such as schizophre-nia, Parkinson’s disease, attention deficit hyperactivity disorder,and depression (Diamond, 1996; El-Ghundi et al., 1999; Foltynieet al., 2004; Reuter et al., 2005; Williams-Gray, Hampshire, Rob-bins, Owen, & Barker, 2007; Dremencov, el Mansari, & Blier,2009). In humans and rodents, the relationship between dopamine

signaling and cognitive performance is best described as a dose-dependent, inverted-U curve whereby an excess or an insufficiencyof dopamine can lead to detrimental effects (see Figure 1)(Goldman-Rakic, Muly, & Williams, 2000; Williams-Gray et al.,2007; Monte-Silva et al., 2009). Previous studies have indicatedthat the inverted U relation is associated with genetic variation incatechol-O-methyltransferase (COMT), a key regulatory enzymethat degrades dopamine and thus controls dopamine availability(Axelrod & Tomchick, 1958; Goldberg & Weinberger, 2004).

Yufei A. Cao, Robert E. Featherstone, Michael J. Gandal, YulingLiang, Catherine Jutzeler, John Saunders, Valerie Tatard-Leitman, andSteven J. Siegel, Translational Neuroscience Program, Department ofPsychiatry, University of Pennsylvania; Jingshan Chen and Daniel R.Weinberger, Clinical Brain Disorders Branch, Genes, Cognition andPsychosis Program, National Institute of Mental Health, Bethesda,Maryland; Caryn Lerman, Center for Research on Nicotine Addiction,Department of Psychiatry, University of Pennsylvania.

Supported by Grant 1-P50-DA143187; Academic Development Funds,to University of Pennsylvania; and the Genes, Cognition and PsychosisProgram, National Institute of Mental Health. Yufei Cao, Robert Feather-

stone, Michael Gandal, Yuling Liang, Catherine Jutzeler, John Saunders,Jingshan Chen, and Daniel Weinberger have no financial conflicts ofinterest; Caryn Lerman has been a consultant and/or has received grantsupport from the following companies that develop and/or market smokingcessation medications: Astra Zeneca, Glaxo SmithKline, Novartis, andPfizer; Steven Siegel has been a consultant and/or has received grantsupport from the following companies that develop and/or market medi-cations: NuPathe, AstraZeneca, and Merck.

Correspondence concerning this article should be addressed to Steven J.Siegel, M.D., Ph.D., Department of Psychiatry, Room 2202, TranslationalResearch Laboratories, 125 South 31st Street, University of Pennsylvania,Philadelphia, PA 19104, E-mail: siegels@upenn.edu

Behavioral Neuroscience © 2012 American Psychological Association2012, Vol. ●●, No. ●, 000–000 0735-7044/12/$12.00 DOI: 10.1037/a0027047

1

COMT is particularly important in regions such as the prefrontalcortex, where the density of dopamine transporters is relativelylow (Mazei, Pluto, Kirkbride, & Pehek, 2002; Moron, Brocking-ton, Wise, Rocha, & Hope, 2002; Matsumoto et al., 2003). COMTcontains a common, functional sequence variation in a singlenucleotide polymorphism that results in a valine to methioninesubstitution at codon 158. This leads to upward of a twofoldincrease in enzymatic activity and dopamine catabolism, therebysignificantly reducing basal dopamine levels in COMT-Val carriers(Chen et al., 2004).

A genetic association between COMT and schizophrenia hasbeen observed in a number of studies, but the association isstatistically weak and inconsistent. More consistently, however,this COMT polymorphism has been shown to contribute to differ-ences in cortical dopamine and to influence cognition both innormal subjects and in patients with schizophrenia. Studies havesuggested that working memory deficits characteristic of patientswith schizophrenia are also heritable and associated with suscep-tibility to the disease (Goldberg et al., 2003). In a study by Eganet al. (2001), the COMT-Val/Met variant was predictive of exec-utive function performance on the Wisconsin Card Sorting Test,with patients with schizophrenia carrying the COMT-Val alleledemonstrating worse cognitive performance. Similarly, executivefunction is significantly altered by COMT genotype in patientswith Parkinson’s disease and depression. However, the genotype-�phenotype relationship is reversed in Parkinson’s disease suchthat the high-activity allele confers a cognitive advantage (Foltynieet al., 2004; Williams-Gray et al., 2007). Because catecholaminedysfunction is involved in various neurological disorders, theCOMT enzyme and gene provide potential targets for pharmaco-logical treatments.

In addition to displaying cognitive impairments, patients withseveral psychiatric disorders often exhibit an increased tendency tosmoke tobacco (Pomerleau, Downey, Stelson, & Pomerleau, 1995;Esterberg, Jones, Compton, & Walker, 2007). This is especiallytrue for people with schizophrenia, in whom the prevalence of

tobacco consumption is nearly 90% (Hughes, Hatsukami, Mitchell,& Dahlgren, 1986). Although the precise reasons for this increasein smoking frequency are not well understood, studies have sug-gested that nicotine may improve cognitive functions that arecritically affected in schizophrenia, such as attention and workingmemory (Cattapan-Ludewig, Ludewig, Jaquenoud Sirot, Etzens-berger, & Hasler, 2005). Hence, nicotine-induced cognitive im-provement may be a motivational factor driving this behavior(Kumari & Postma, 2005; Amitai & Markou, 2009). Furthermore,a number of studies have shown that among people with andwithout schizophrenia, carriers of the COMT-Val allele are morelikely to develop nicotine dependence and be less responsive tonicotine replacement therapy (Addington, el-Guebaly, Addington,& Hodgins, 1997; George et al., 2000; George et al., 2002; Colillaet al., 2005; Beuten, Payne, Ma, & Li, 2006). Moreover, smokerswith the COMT-Val/Val genotype are more prone to nicotineabstinence-induced cognitive deficits and decreased prefrontal ac-tivity during performance of working memory tasks (Loughead etal., 2009). Because nicotine stimulates the release of corticaldopamine, this may counteract the excessive dopamine inactiva-tion by the high-activity COMT-Val variant. Thus, nicotine issuggested to reestablish a more optimal dopaminergic balance bypotentiating dopamine release, thereby attenuating cognitive def-icits (Pontieri, Tanda, Orzi, & Di Chiara, 1996; Lyon, 1999).

Cognitive impairments have been associated with changes inneural oscillations, which in turn are also associated with ge-netic polymorphisms in the dopamine pathway (Venables, Ber-nat, & Sponheim, 2009). Additionally, electrophysiologicalstudies have indicated that gamma and theta oscillations medi-ate cognitive processes in mammalian brains (Herrmann, Frund,& Lenz, 2010). Growing evidence has indicated that oscillatorybrain activity is disturbed in patients of schizophrenia. In par-ticular, reduced evoked power as well as impaired synchrony inthe theta and gamma frequency ranges have been consistentlyreported (Uhlhaas & Singer, 2010; Gandal, Edgar, Klook, &Siegel, 2011). Furthermore, nicotine has been reported to re-store the aforementioned electrophysiological deficits, presum-ably by enhancing dopamine neurotransmission (Gray, Rajan,Radcliffe, Yakehiro, & Dani, 1996; Akkurt, Akay, & Akay,2010; Lu & Henderson, 2010).

The present study employed transgenic mice expressing thehuman COMT-Val variant to determine the effects of the addi-tional high-activity COMT allele on electrophysiological mark-ers of sensory processing, including the P20, N40, and P80components of the auditory event-related potential (ERP), aswell as on baseline and auditory event-related power and phasesynchrony in theta and gamma frequency ranges. We alsoexamined the effects of nicotine on these measures, to investi-gate the potential effects of smoking on altered electrophysio-logical activity implicated in patients with schizophrenia. Wetested the following hypotheses:

1. COMT-Val-tg mice will manifest a reduction in the am-plitude of ERP components that have been associatedwith cognitive function, including the P80, which is themouse analog of the human P200 (Umbricht et al., 2004).

2. The high-activity COMT-Val-tg mice will have increasedP80 ERP latency, similar to humans with the high-

Figure 1. Graphic representation of proposed inverted-U relationshipbetween dopamine neurotransmission and cognitive efficiency. Note thatnicotine is proposed to move organisms with the high-activity COMT-Valallele to a more optimal level of function by restoring optimal dopamineavailability. WT � wild-type.

2 CAO ET AL.

activity Val allele, and patients with schizophrenia, Par-kinson’s disease, mild cognitive impairment, and familialAlzheimer’s disease (Tsai et al., 2003; Missonnier et al.,2007; Golob et al., 2009; Kang, Xu, Liu, & Yang, 2010).

3. COMT activity will modulate neural oscillatory activityin a manner consistent with its effects on cognition inhumans (Bramon et al., 2006; Cooray, Maurex, & Bris-mar, 2008). Specifically, we anticipated a reduction theta,without changes in gamma activity among COMT-Valsubjects, as previously found in human clinical studies(Demiralp et al., 2007; Venables et al., 2009).

4. Nicotine will increase amplitude of the P20, decreaseamplitude of the N40, and increase amplitude of the P80,consistent with previous findings (Siegel et al., 2005;Metzger, Maxwell, Liang, & Siegel, 2007; Phillips, Eh-rlichman, & Siegel, 2007).

5. Nicotine will normalize the COMT-mediated reductionin P80 ERP amplitude and increased in P80 latency,presumably by increasing dopamine release among ani-mals with low basal dopamine levels. Additionally, nic-otine will reverse COMT-mediated alterations in gammaand theta time-frequency measures.

Method

Animals

The COMT-Val-tg mice were obtained from the intramuralprogram at the National Institute of Mental Health, and a breedingcolony was established at the University of Pennsylvania. COMT-Val transgenic mice were crossbred with neuron-specific enolase(NSE)-tetracycline transactivator (tTA) transgenic mice to bringthe COMT-Val and tTA transgenes together and achieve tissue-specific expression. Single transgenic COMT-Val mice, NSE-tTAmice, and mice carrying neither transgene were pooled together inthe control group as previously described (Papaleo et al., 2008).Mice were identified by polymerase chain reaction analysis of tailDNA. Animals were maintained on a 12-h light�dark cycle in atemperature-controlled facility with food and water available adlibitum. Mice were housed four to five per cage and acclimated tothe housing facility for at least 1 week before electrode implanta-tion. After electrode placement, each mouse was housed individ-ually. All protocols were approved by the University of Pennsyl-vania Institutional Animal Care and Use Committees. A total of 42animals were used as follows: nine transgenic females, 10 trans-genic males, 11 wild-type littermate females, and 10 wild-typelittermate males.

Electrode Implantation

Animals were anesthetized with isofluorane prior to and duringelectrode implantation. Differential (positive, negative, andground) recording electrodes (Plastic One Inc.) were stereotaxi-cally implanted in the right CA3 region of the hippocampus (1.8mm posterior, 2.65 mm lateral, and 2.75 mm deep relative to thebregma) and were referenced to the ipsilateral frontal sinus. The

electrode pedestal was secured to the skull with ethyl cyanoacry-late (Loctite, Henkel KGaA) and dental cement (Ortho-Jet BCA,Lang Dental Manufacturing). Following implantation, all animalswere allowed to recover for at least 1 week prior to recording. Allprocedures were consistent with previously published methodolo-gies (Connolly et al., 2003; Maxwell et al., 2004; Siegel et al.,2005; Metzger et al., 2007).

Recording

ERP and frequency-related recordings were conducted in thehome cage environment placed in a Faraday cage. Auditorystimuli were generated by Micro1401 hardware and Spike2,version 6.0 software (Cambridge Electronic Design) and weredelivered through speakers attached to the cage top. The re-cording session consisted of three trials. Animals were habitu-ated to the testing setting for 15 min prior to stimulus onset forthe first, baseline, trial. Animals then received a 0.1-ml intra-peritoneal injection of 0.09% saline 5 min prior to stimulusonset during the second trial. Animals then received a 0.1-mlintraperitoneal injection of nicotine hydrogen tartrate salt(Sigma-Aldrich) dissolved in 0.09% saline at a dose of 0.5mg/kg 5 min prior to stimulus onset during the third trial. Thedose of nicotine was chosen based on previous studies (Siegelet al., 2005; Metzger et al., 2007; Phillips et al., 2007). Thestimulus protocol consisted of 50 paired white-noise bursts(10-ms duration, 500-ms intrapair interval) with a 9-s interpairinterval presented at 85 dB compared to a 70-dB white-noisebackground. Individual ERP waveforms were sampled at 1667Hz, filtered between 1 and 500 Hz, and rejected for movementartifact based on the criterion of two times the root meansquared amplitude per mouse. Average waveforms for individ-ual mice were baseline corrected at 0 ms poststimulus. Grandaverage waves were then produced from 0 to 300 ms afterstimulus onset.

Electroencephalographic Data Analysis

ERP amplitude and latency. The amplitudes and latenciesof three auditory-evoked potential components were calculatedfollowing the response to the first stimulus for each mouse atbaseline, postsaline, and postnicotine (0.5 mg/kg) (see Figure2). The first component, the P20, is a positive deflection be-tween 15 and 35 ms, and is proposed to be the mouse analog ofthe human P50 (Connolly et al., 2003; Siegel et al., 2003). Thesecond component, named the N40, is defined as the troughbetween 25 and 60 ms, similar to the human N100 (Maxwell etal., 2004). A third component, termed the P80, is defined as apositive deflection between 60 and 300 ms directly after theN40 and displays response properties similar to the human P200(Siegel et al., 2003). The amplitudes of the P20 and P80components of the ERP waveform were chosen by determiningthe maximum positive deflection between 15 and 35 ms andbetween 60 and 300 ms, respectively. The amplitude of the N40component was chosen by determining the maximum negativedeflection between 25 and 55 ms. The latency for each com-ponent was defined as the time poststimulus at which its max-imum deflection occurred. Analysis of variance (ANOVA) wasperformed on baseline- and artifact-corrected data for the am-

3NICOTINE NORMALIZES ERPs IN MICE

plitude of each ERP component to identify interactions betweenstimulus, genotype, sex, and treatment condition, as well asmain effects. Similarly, ANOVAs were performed on data forlatency of each component to identify interactions betweennicotine and genotype and sex, and main effects. All dataanalyses were performed using Statistica, version 6.1 (StatSoftInc.) with significance set at p � .05.

Time-frequency analysis. Spectral decomposition ofauditory-evoked response waveforms was performed using theEEGLAB toolbox in Matlab, as published (Delorme & Makeig,2004; Gandal et al., 2010). Single-trial epochs between �0.3and 0.8 s relative to the first stimulus (S1) were extracted fromthe continuous electroencephalographic data sampled at 1667Hz. For each epoch, total power (i.e., event-related spectral

perturbation, ERSP) and phase-locking factor (PLF) values(i.e., intertrial coherence) were calculated using Morlet wave-lets in 100 linearly spaced frequency bins between 5.0 and 100Hz, with wavelet cycles increasing from 3 (at low frequencies)to 6 (at high frequencies). Total power was calculated in deci-bels relative to baseline power (�200 to 0 ms) in each fre-quency band. PLF is expressed as a unitless ratio between 0 and1, where 1 represents complete phase synchrony at a givenfrequency and time across trials. Auditory event-related oscil-lations were averaged across low (theta: 5–12 Hz) and high(gamma: 30 –100 Hz) frequencies from 0 –100 ms poststimulus.In addition to auditory-evoked activity, measures of baselinepower spectral density were calculated using Welch’s method(window length 512, fast Fourier transform length 1024, 0%

Figure 2. Examples of event-related potentials from a single mouse in the control (saline) condition (a) and asa grand average of all traces (b). P20, N40, and P80 are noted.

4 CAO ET AL.

overlap, 1.63-Hz steps) on 60 s of stimulus-free electroenceph-alographic signal.

Statistics

Statistical analysis of time- and frequency-domain ERP mea-sures was assessed using Group � Sex � Drug � FrequencyANOVA. Significant interactions were followed by Fisher’s leastsignificant difference posttests, where appropriate.

Results

Event-Related Potentials

P20 amplitude and latency. Consistent with previous find-ings, there was a significant main effect of nicotine on P20amplitude and latency, with nicotine resulting in both a greater P20amplitude and a longer P20 latency compared with controls (p �.029, p � .001; Figure 3) (Metzger et al., 2007; Amann, Phillips,Halene, & Siegel, 2008). There was also an effect of sex for theP20 amplitude, which approached statistical significance (p �.056), with males exhibiting greater amplitude than females. Fi-nally, there was a trend for an effect of genotype on P20 latency,which also approached significance (p � .069), with the COMT-Val-tg mice revealing a longer P20 latency compared with theirwild-type littermates. There were no significant interactions be-tween genotype and treatment, or sex and treatment for either P20amplitude or latency.

N40 amplitude and latency. There were significant maineffects of nicotine on N40 amplitude (p � .001) and latency (p �.018), with nicotine attenuating N40 amplitude and increasing N40latency, consistent with previously published data (Phillips et al.,2007; Amann et al., 2008). There was also a significant effect ofgenotype on N40 latency (p � .039; Figure 4), with the COMT-Val-tg mice exhibiting longer N40 latency than their wild-typelittermates. There were no significant interactions between geno-type and treatment condition, or between sex and treatment con-dition on N40 amplitude or latency.

P80 amplitude and latency. Analysis of P80 amplituderevealed a significant effect of genotype (p � .003), with wild-type mice exhibiting greater P80 amplitude than the COMT-Val-tgmice. There was also a significant main effect of nicotine on thismeasure (p � .001). There was no significant interaction betweengenotype and treatment condition (p � .602). Of note, nicotineincreased P80 amplitude of the COMT-Val-tg mice to match thelevel of wild-type littermates on saline treatment (see Figure 5).The COMT-Val-tg mice demonstrated qualitatively longer P80latency than their wild-type littermates, although the differencewas not significant (data not shown). Analysis of P80 latency alsorevealed a significant main effect of nicotine on P80 latency, withbaseline and saline-treated animals displaying a longer P80 latencythan nicotine treated (p � .001; see Figure 2a).

Electroencephalographic Time-Frequency Analyses

Theta and gamma spectral power. Time-frequency plots foreach condition are shown in Figure 6. ANOVA revealed a signif-icant genotype effect on baseline power in the theta and gammafrequency ranges, with the COMT-Val-tg mice exhibiting lowertotal power than their wild-type littermates (theta: p � .042,gamma: p � .034; Figure 7). Furthermore, there was a significantreduction in baseline power postnicotine in the theta and gammabands, in both groups of mice (p � .001 for both frequencyranges). No sex or interaction effects were observed.

No genotype or sex effect was observed for poststimulus power.However, nicotine significantly increased auditory-evoked powerin the theta and gamma frequency ranges in the COMT-Val-tgmice and the wild-type littermates (p � .001; Figure 8a, b). Nointeractions among gene, sex, and nicotine conditions were ob-served.

Theta and gamma phase synchrony. No genotype or sexeffects were observed for PLF (i.e., intertrial coherence). Similarto evoked power, nicotine significantly increased PLF in the thetaand gamma ranges in COMT-Val-tg and wild-type mice (thetaPLF: p � .01, gamma PLF: p � .001, see Figure 8c, d). There wereno main effects or interactions involving sex for any measure ofoscillatory activity.

Discussion

This study examined the effects of nicotine treatment onelectroencephalographic-related outcome measures in COMT-Val-tg mice and their wild-type littermates. The effects of nicotineincluded an increase in P20 and P80 amplitudes, a decrease in N40amplitude, a lengthening of P20 and N40 latencies, and a reductionin P80 latency. Nicotine also reduced baseline power, while in-creasing both the auditory-evoked power (ERSP) and phase syn-

Figure 3. Analysis of the effects of nicotine on P20, N40, P80 amplitudesand latencies. Nicotine increased P20 and N40 latencies, and decreasedP80 latency relative to saline control injections. There was no significantdifference between baseline (no injection) and saline injections (a). Nico-tine increased P20 and P80, while decreasing N40 amplitude (b). Error barsrepresent standard error of the mean, � p � .05. ��� p � .001.

5NICOTINE NORMALIZES ERPs IN MICE

chrony (PLF), yielding an increase in signal-to-noise ratio acrosstheta and gamma frequency ranges.

The current data in mice are consistent with previous studies inhumans that have examined the association of COMT genotypewith ERP measures. Although no data are available on the effectsof COMT polymorphisms on P50 or N100 amplitude or latency,previous studies have shown that COMT-Val/Met genotype doesnot alter P50 gating, consistent with the lack of change in P20presently described (Majic et al., 2011; Shaikh et al., 2011).Alternatively, previous studies have suggested that Met/Met indi-viduals demonstrated poorer N100 gating compared to Val/Metand Val/Val individuals (Majic et al., 2011). Previous studies havealso suggested that COMT activity is associated with task-relatedP300 amplitude (Golimbet et al., 2006; Yue, Wu, Deng, Wang, &Sun, 2009; Kang et al., 2010). However, no findings have previ-ously addressed the effects of COMT activity on long latencyobligatory ERPs, including the P200, that are independent of taskperformance. Data in the current study suggest that COMT activityhas a direct effect on encoding of obligatory long latency compo-nents, and may represent a primary alteration in bottom-up pro-cessing. Furthermore, these data indicate that reduced P80 ampli-tude in COMT-Val-tg mice is consistent with correspondingalterations in human disorders that are thought to involve altera-tions of dopamine neurotransmission. Specifically, clinical studieshave demonstrated decreased P200 amplitude in patients withschizophrenia, depression, and Parkinson’s disease (Roth, Pfeffer-baum, Kelly, Berger, & Kopell, 1981; Lagopoulos et al., 1998;Williams, Gordon, Wright, & Bahramali, 2000).

In Parkinson’s disease, reduced dopaminergic activity is thoughtto contribute to cognitive dysfunction, especially deficits in exec-utive function, working memory, planning, and attentional setshifting (Lange et al., 1992; Owen et al., 1992). Modern treatmentsused for managing Parkinson’s disease fall within three categories:direct agonists, such as ropinirole, which bind dopamine receptors;indirect agonists such as levodopa (L-dopa), which serves as aprecursor of dopamine synthesis; and COMT inhibitors, such astolcapone, to prevent dopamine metabolism. Indeed, tolcapone hasbeen found to improve cognitive performance in healthy individ-uals who carry the valine allele (Giakoumaki, Roussos, & Bitsios,2008). These data are consistent with the dopamine homeostasis

mechanism in which restoring normal dopamine levels alleviatescognitive deficits. Similarly, medications that inhibit dopaminereuptake, such as bupropion, have been shown to be efficacious inboth depression and smoking cessation. This suggests an associa-tion of psychiatric disorders and nicotine dependence with adopamine-dependent endophenotype involving suboptimal corticaldopamine function (Weinberger, Berman, & Illowsky, 1988; Da-vis, Kahn, Ko, & Davidson, 1991).

Increased COMT activity has also been associated with cogni-tive deficits in schizophrenia, presumably by decreasing dopamineat D1 receptors in the prefrontal cortex (Slifstein et al., 2008).Clinical studies have also demonstrated reduced P200 amplitude inpatients with schizophrenia, consistent with data in patients withdepression and Parkinson’s disease (Roth et al., 1981; Shenton etal., 1989; Lagopoulos et al., 1998; Williams et al., 2000). Thesedata implicate an association between reduced cortical dopamineand decreased P200 amplitude, suggesting that reduced P200 am-plitude may be an appropriate biomarker for dopamine transmis-sion in general, and possible COMT activity in particular. In thecurrent study, we observed lower P80 amplitude in COMT-Val-tgmice, compared to their wild-type littermates. We also observedincreases in P80 amplitude in response to nicotine in both groups,consistent with previous data on the effects of nicotine on ERPcomponent amplitudes (Amann et al., 2008). Although there wasno significant interaction between the COMT gene and nicotine,the nicotine-induced increase in P80 amplitude in the COMT-Val-tg group is noteworthy. Specifically, the P80 amplitude of theCOMT-Val-tg group after nicotine administration was similar tothe level of the wild-type littermates at baseline and after saline.This suggests a normalization effect of nicotine on the P80 am-plitude in COMT-Val-tg mice, consistent with the hypothesis thatnicotine reestablishes normal dopaminergic balance in individualswith the high-activity allele (Lyon, 1999). The effects of nicotineon P80 presumably functions by the aforementioned mechanism,by potentiating cortical dopamine levels. Conversely, nicotine’seffects on P80 in the wild-type littermates may be disadvantageous

Figure 4. Analysis of COMT-Val-tg on N40 latency. The COMT-Val-tgmice exhibited longer N40 latency across the three treatment conditions.Data are presented as mean � standard error of the mean. WT � wild-type.� p � .05.

Figure 5. Analysis of COMT-Val-tg and nicotine effects on P80 ampli-tude. Mice with the COMT-Val-tg exhibited reduced P80 amplitude for allthree treatment conditions. However, nicotine increased P80 amplitude ofthe COMT-Val-tg mice to a level comparable to that of control littermatesin the prenicotine conditions. WT � wild-type. �� p � .01. ��� p � .001.

6 CAO ET AL.

with respect to the proposed inverted-U relationship between do-pamine levels and cognition.

ERP component latency has been used as a surrogate marker ofprocessing speed, and previous data has suggested that increasinglatency represents a deficit in neural processing efficiency (OramCardy, Flagg, Roberts, & Roberts, 2008). Numerous studies have

demonstrated that processing speed correlates directly with IQscores and possibly with reasoning ability (Sen, Jensen, Sen, &Arora, 1983; Baker, Vernon, & Ho, 1991; Rijsdijk, Vernon, &Boomsma, 1998). Specifically, reduced late-component ERP la-tencies have been associated with enhanced cognitive perfor-mance. This particularly applies to the human P300 (Sahai, Tan-

Figure 6. Examples of time-frequency plots with time along the x axis and frequency along the y axis.Individual plots are shown for males (M) and females (F) in each genotype (WT or COMT) and following eithersaline (SAL) or nicotine (NIC). Power is expressed in decibels, as shown in the upper right corner. WT �wild-type.

Figure 7. Analysis of the effects of COMT-Val-tg on total power. COMT-Val-tg mice exhibit lower baselinepower than their wild-type (WT) littermates for theta and gamma power (a). There was also a significantreduction in baseline power postnicotine in the theta (b) and gamma (c) ranges across both groups of mice. � p �.05. ��� p � .001.

7NICOTINE NORMALIZES ERPs IN MICE

don, & Sircar, 2000; Wright et al., 2002). Because thetemporal�parietal cortex is one of the primary generators of bothP300 and P200, several studies have suggested that shortened P200latency is also related to cognitive improvements (Knight, Scabini,Woods, & Clayworth, 1989; Verleger, Heide, Butt, & Kömpf,1994; Sheehan, McArthur, & Bishop, 2005). In the present study,the COMT-Val-tg mice demonstrated qualitatively longer P80 la-tency than their wild-type littermates, although the difference wasnot significant. Further, the P80 latency of both groups was re-duced in response to nicotine, which was more pronounced for theCOMT-Val-tg group. These data suggest a potential mechanism forimprovement in cognitive performance following nicotine, consis-tent with the effects of nicotine on cortical dopamine elevation.Furthermore, N40 latency was longer in COMT-Val-tg mice, sug-gesting a common neural mechanism for the effects of COMTactivity across cortical potentials.

Neural synchrony has recently emerged as an important featureof brain activity in the study of schizophrenia. Measures of thetaand gamma activity have been shown to be affected in schizophre-nia, and these deficits have been shown to be heritable (Hong et al.,2008; Hall et al., 2009). Theta power is reduced in patients withschizophrenia and is associated with memory deficits seen in theillness (Davalos, Kisley, Polk, & Ross, 2003; Schmiedt, Brandl,Hildebrandt, & Basar-Eroglu, 2005; Brockhaus-Dumke, Mueller,Faigle, & Klosterkoetter, 2008; Ramos-Loyo, Gonzalez-Garrido,Sanchez-Loyo, Medina, & Basar-Eroglu, 2009). Additionally, re-duced gamma power is thought to underlie the types of sensoryprocessing and cognitive deficits that are common among peoplewith schizophrenia (Kwon et al., 1999; Lee, Williams, Haig,Goldberg, & Gordon, 2001; Light et al., 2006; Leicht et al., 2010).Here, we have demonstrated reduced baseline power spectral den-sity in the theta and gamma frequency ranges in the COMT-Val-tg

group. Despite the preponderance of clinical data for oscillatorymeasures, a few studies have investigated the direct effects of theCOMT genotype on theta and gamma power. One study has shownthat Met-Met (low-activity) patients with schizophrenia demon-strated augmented theta activity, consistent with our finding (Ven-ables et al., 2009). PLF is a measure of phase coherence acrosstrials that is independent of oscillatory amplitude and therefore isa direct measure of neural synchronization. Clinical studies ofschizophrenia have described disrupted neural synchrony, consis-tent with data from a genetic mouse model of schizophrenia thatshowed a reduction in phase-locking after microdeletion of aschizophrenia risk allele, 22q11.2 (Sigurdsson, Stark, Karay-iorgou, Gogos, & Gordon, 2010). We anticipated that the COMT-Val-tg mice might also demonstrate reduced phase-locking(Bearden et al., 2005). Contrary to our expectation, we found nosignificant differences between genotypes in theta or gamma PLF.However, there were significant differences in recording method-ologies and calculation of phase-synchrony between our study andthe previous one, which could limit the direct comparison ofresults. Nevertheless, this suggests that changes in COMT aloneare not sufficient to explain the observed differences in 22q11.2-deficient mice, or likely in schizophrenia.

In addition to changes in baseline theta and gamma activity, wealso evaluated changes in spectral response to nicotine. Nicotinehas been shown to reduce baseline theta power, consistent with ourfindings in the present study (Lindgren, Molander, Verbaan,Lunell, & Rosen, 1999; Knott & Fisher, 2007). We also demon-strated increased auditory-evoked gamma activity after acute nic-otine treatment, consistent with previous studies (Phillips et al.,2007). Here, we also demonstrated decreased baseline gammapower, suggesting increased signal-to-noise ratio for gamma ac-tivity. Consistent with these findings, several studies have dem-onstrated that nicotine increases cognitive ability in a variety oftasks and measures related to attention and memory, presumablyby potentiating cortical dopamine release (Froeliger, Gilbert, &McClernon, 2009; Rusted, Sawyer, Jones, Trawley, & Marchant,2009). Alternatively, there was no effect of COMT-Val-tg on thisrelationship in the current study, suggesting that the effect ofnicotine may not be mediated entirely by dopamine availability.

The effects of COMT and nicotine on ERP and electroenceph-alographic signals are hypothesized to occur largely though theeffects of each on dopamine release and metabolism. Althoughdopamine likely plays a key role in observed changes in ERPs andtheta and gamma power, there are several other important neu-rotransmitter systems that should be considered, possibly via up-stream dopamine action. Work from several groups has suggestedthat both glutamate and gamma-aminobutyric acid (GABA) sys-tems are involved in the generation and modulation of ERPs andhigh (gamma) and low (theta) frequency oscillations. Multiplestudies have implicated dopamine and other monoamines, such asserotonin and norepinephrine, as well as GABA, glutamate, andstress hormones in modulating the amplitude and latency of ERPs(Siegel et al., 2003; Maxwell et al., 2004; Siegel et al., 2005;Maxwell, Ehrlichman, Liang, Gettes, et al., 2006; Maxwell, Eh-rlichman, Liang, Trief, et al., 2006; Amann et al., 2008; Amann etal., 2009; Bodarky et al., 2009; Gandal et al., 2010). Additionalstudies in mice have suggested that alterations in glutamate andGABA transmission can alter both power and synchrony (PLF)(Ehrlichman et al., 2009; Gandal et al., 2010; Lazarewicz et al.,

Figure 8. Analysis of auditory event-related power and phase locking.Nicotine increases event related power in the theta (a) and gamma (b)ranges as well as theta phase-locking factor (PLF) (c) and gamma PLF (d).ERSP � event-related spectral perturbation. �� p � .01. ��� p � .001.

8 CAO ET AL.

2010; Belforte et al., 2010; Gandal et al., 2011). Consistent withthese findings, alterations in GABA cell populations that contain arelatively high proportion of glutamate receptors have been dem-onstrated in postmortem brains of patients with schizophrenia, whoexhibited a pattern of increased resting and decreased evokedgamma power (Beasley & Reynolds, 1997; Reynolds, Abdul-Monim, Neill, & Zhang, 2004; Gandal et al., 2011). Taken to-gether, these data suggest that alterations in ERPs and electroen-cephalographic patterns in the current study may reflect thecomplex interaction of multiple neurotransmitter systems.

Conclusion

The current study demonstrates that COMT activity specificallyalters long-latency components of the event-related response, con-sistent with known effects on cognition. Similarly, nicotine re-stored normal event-related activity among COMT-Val-tg mice,suggesting that nicotine may normalize cognitive function amongpeople with the high-activity allele. Similarly, nicotine increasedthe gamma signal-to-noise ratio. Of note, people with schizophre-nia have both elevated baseline and reduced gamma activity,suggesting that nicotine may normalize this measure of impairedbrain activity. These findings may have implications for the treat-ment of nicotine dependence in high-risk smokers who carry theCOMT-Val allele.

References

Addington, J., el-Guebaly, N., Addington, D., & Hodgins, D. (1997).Readiness to stop smoking in schizophrenia. The Canadian Journal ofPsychiatry/Revue Canadienne de Psychiatrie, 42(1), 49–52.

Akkurt, D., Akay, Y. M., & Akay, M. (2010). Investigating the synchro-nization of hippocampal neural network in response to acute nicotineexposure. Journal of Neuroengineering and Rehabilitation, 7, 31. doi:10.1186/1743-0003-7-31

Amann, L. C., Halene, T. B., Ehrlichman, R. S., Luminais, S. N., Ma, T.,Abel, T., & Siegel, S. J. (2009). Chronic ketamine impairs fear condi-tioning and produces long-lasting reductions in auditory evoked poten-tials. Neurobiology of Disease, 35, 311–317. doi:10.1016/j.nbd.2009.05.012

Amann, L. C., Phillips, J. M., Halene, T. B., & Siegel, S. J. (2008). Maleand female mice differ for baseline and nicotine-induced event relatedpotentials. Behavioral Neuroscience, 122, 982–990. doi:10.1037/a0012995

Amitai, N., & Markou, A. (2009). Chronic nicotine improves cognitiveperformance in a test of attention but does not attenuate cognitivedisruption induced by repeated phencyclidine administration. Psychop-harmacology, 202, 275–286. doi:10.1007/s00213-008-1246-0

Axelrod, J., & Tomchick, R. (1958). Enzymatic O-methylation of epineph-rine and other catechols. Journal of Biological Chemistry, 233(3), 702–705.

Baker, L. A., Vernon, P. A., & Ho, H. Z. (1991). The genetic correlationbetween intelligence and speed of information processing. BehaviorGenetics, 21, 351–367. doi:10.1007/BF01065972

Bearden, C. E., Jawad, A. F., Lynch, D. R., Monterossso, J. R., Sokol, S.,McDonald-McGinn, D. M., . . . Simon, T. J. (2005). Effects of COMTgenotype on behavioral symptomatology in the 22q11.2 Deletion Syn-drome. Child Neuropsychology, 11, 109 –117. doi:10.1080/09297040590911239

Beasley, C. L., & Reynolds, G. P. (1997). Parvalbumin-immunoreactiveneurons are reduced in the prefrontal cortex of schizophrenics. Schizo-phrenia Research, 24, 349–355. doi:10.1016/S0920-9964(96)00122-3

Belforte, J. E., Zsiros, V., Sklar, E. R., Jiang, Z., Yu, G., Li, Y., . . .Nakazawa, K. (2010). Postnatal NMDA receptor ablation in corticolim-bic interneurons confers schizophrenia-like phenotypes. Nature Neuro-science, 13, 76–83. doi:10.1038/nn.2447

Beuten, J., Payne, T. J., Ma, J. Z., & Li, M.D. (2006). Significant associ-ation of catechol-O-methyltransferase (COMT) haplotypes with nicotinedependence in male and female smokers of two ethnic populations.Neuropsychopharmacology, 31, 675–684. doi:10.1038/sj.npp.1300997

Bodarky, C. L., Halene, T. B., Ehrlichman, R. S., Banerjee, A., Ray, R.,Hahn, C. G., . . . Siegel, S. J. (2009). Novel environment and GABAagonists alter event-related potentials in N-methyl-D-aspartate NR1 hy-pomorphic and wild-type mice. The Journal of Pharmacology andExperimental Therapeutics, 331, 308–318. doi:10.1124/jpet.109.150938

Bramon, E., Dempster, E., Frangou, S., McDonald, C., Schoenberg, P.,MacCabe, J. H., . . . Murray, R. M. (2006). Is there an associationbetween the COMT gene and P300 endophenotypes? European Psychi-atry, 21, 70–73. doi:10.1016/j.eurpsy.2005.11.001

Brockhaus-Dumke, A., Mueller, R., Faigle, U., & Klosterkoetter, J. (2008).Sensory gating revisited: Relation between brain oscillations and audi-tory evoked potentials in schizophrenia. Schizophrenia Research, 99,238–249. doi:10.1016/j.schres.2007.10.034

Cattapan-Ludewig, K., Ludewig, S., Jaquenoud Sirot, E., Etzensberger, M.,& Hasler, F. (2005). [Why do schizophrenic patients smoke?] [German].Der Nervenarzt, 76, 287–294. doi:10.1007/s00115-004-1818-0

Chen, J., Lipska, B. K., Halim, N., Ma, Q. D., Matsumoto, M., Melhem, S.,. . . Weinberger, D. R. (2004). Functional analysis of genetic variation incatechol-O-methyltransferase (COMT): effects on mRNA, protein, andenzyme activity in postmortem human brain. American Journal of Hu-man Genetics, 75, 807–821. doi:10.1086/425589

Colilla, S., Lerman, C., Shields, P. G., Jepson, C., Rukstalis, M., Berlin, J.,. . . Rebbeck, T. R. (2005). Association of catechol-O-methyltransferasewith smoking cessation in two independent studies of women. Pharma-cogenetic Genomics, 15, 393–398. doi:10.1097/01213011-200506000-00004

Connolly, P. M., Maxwell, C. R., Kanes, S. J., Abel, T., Liang, Y.,Tokarczyk, J., . . . Siegel, S. J. (2003). Inhibition of auditory evokedpotentials and prepulse inhibition of startle in DBA/2J and DBA/2Hsdinbred mouse substrains. Brain Research, 992, 85–95. doi:10.1016/j.brainres.2003.08.035

Cooray, G. K., Maurex, L., & Brismar, T. (2008). Cognitive impairmentcorrelates to low auditory event-related potential amplitudes in type 1diabetes. Psychoneuroendocrinology, 33, 942–950. doi:10.1016/j.psyneuen.2008.04.013

Davalos, D. B.,. Kisley, M. A., Polk, S., & Ross, R. G. (2003). Mismatchnegativity in detection of interval duration deviation in schizophrenia.NeuroReport: For Rapid Communication of Neuroscience Research, 14,1283–1286. doi:10.1097/00001756-200307010-00019

Davis, K. L., Kahn, R. S., Ko, G., & Davidson, M. (1991). Dopamine inschizophrenia: A review and reconceptualization. The American Journalof Psychiatry, 148(11), 1474–1486.

Delorme, A., & Makeig, S. (2004). EEGLAB: An open source toolbox foranalysis of single-trial EEG dynamics including independent componentanalysis. Journal of Neuroscience Methods, 134, 9–21. doi:10.1016/j.jneumeth.2003.10.009

Demiralp, T., Herrmann, C. S., Erdal, M. E., Ergenoglu, T., Keskin, Y. H.,Ergen, M., & Beydagi, H. (2007). DRD4 and DAT1 polymorphismsmodulate human gamma band responses. Cerebral Cortex, 17, 1007–1019. doi:10.1093/cercor/bhl011

Diamond, A. (1996). Evidence for the importance of dopamine for pre-frontal cortex functions early in life. Philosophical Transactions of theRoyal Society of London. Series B: Biological Sciences, 351, 1483–1493. doi:10.1098/rstb.1996.0134

Dremencov, E., el Mansari, M., & Blier, P. (2009). Brain norepinephrinesystem as a target for antidepressant and mood stabilizing medications.

9NICOTINE NORMALIZES ERPs IN MICE

Current Drug Targets, 10, 1061–1068. doi:10.2174/138945009789735165

Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti,C. M., Straub, R. E., . . . Weinberger, D. R. (2001). Effect of COMTVal108/158 Met genotype on frontal lobe function and risk for schizo-phrenia. Proceedings of the National Academy of Sciences of the UnitedStates of America, 98, 6917–6922. doi:10.1073/pnas.111134598

Ehrlichman, R. S., Gandal, M. J., Maxwell, C. R., Lazarewicz, M. T.,Finkel, L. H., Contreras, D., . . . Siegel, S. J. (2009). N-methyl-D-asparticacid receptor antagonist-induced frequency oscillations in mice recreatepattern of electrophysiological deficits in schizophrenia. Neuroscience,158, 705–712. doi:10.1016/j.neuroscience.2008.10.031

El-Ghundi, M., Fletcher, P. J., Drago, J., Sibley, D. R., O’Dowd, B. F., &George, S. R. (1999). Spatial learning deficit in dopamine D(1) receptorknockout mice. European Journal of Pharmacology, 383, 95–106. doi:10.1016/S0014-2999(99)00573-7

Esterberg, M. L., Jones, E. M., Compton, M. T., & Walker, E. F. (2007).Nicotine consumption and schizotypy in first-degree relatives of indi-viduals with schizophrenia and non-psychiatric controls. SchizophreniaResearch, 97, 6. doi:10.1016/j.schres.2007.08.024

Foltynie, T., Goldberg, T. E., Lewis, S. G., Blackwell, A. D., Kolachana,B. S., Weinberger, D. R., . . . Barker, R. A. (2004). Planning ability inParkinson’s disease is influenced by the COMT val158met polymor-phism. Movement Disorders, 19, 885–891. doi:10.1002/mds.20118

Froeliger, B., Gilbert, D. G., & McClernon, F. J. (2009). Effects of nicotineon novelty detection and memory recognition performance: Double-blind, placebo-controlled studies of smokers and nonsmokers. Psycho-pharmacology, 205, 625–633. doi:10.1007/s00213-009-1571-y

Gandal, M. J., Edgar, J. C., Ehrlichman, R. S., Mehta, M., Roberts, T. P.,& Siegel, S. J. (2010). Validating gamma oscillations and delayedauditory responses as translational biomarkers of autism. BiologicalPsychiatry, 68, 1100–1106. doi:10.1016/j.biopsych.2010.09.031

Gandal, M. J., Edgar, J. C., Klook, K., & Siegel, S. J. (2011). Gammasynchrony: Towards a translational biomarker for the treatment-resistantsymptoms of schizophrenia. Neuropharmacology. Advanced online pub-lication.

George, T. P., Vessicchio, J. C., Termine, A., Sahady, D. M., Head, C. A.,Pepper, W. T., . . . Wexler, B. E. (2002). Effects of smoking abstinenceon visuospatial working memory function in schizophrenia. Neuropsy-chopharmacology, 26, 75–85. doi:10.1016/S0893-133X(01)00296-2

George, T. P., Ziedonis, D. M., Feingold, A., Pepper, W. T., Satterburg,C. A., Winkel, J., . . . Kosten, T. R. (2000). Nicotine transdermal patchand atypical antipsychotic medications for smoking cessation in schizo-phrenia. The American Journal of Psychiatry, 157, 1835–1842. doi:10.1176/appi.ajp.157.11.1835

Giakoumaki, S. G., Roussos, P., & Bitsios, P. (2008). Improvement ofprepulse inhibition and executive function by the COMT inhibitor tol-capone depends on COMT Val158Met polymorphism. Neuropsychop-harmacology: Official Publication of the American College of Neuro-psychopharmacology, 33(13), 3058–3068.

Goldberg, T. E., Egan, M. F., Gscheidle, T., Coppola, R., Weickert, T.,Kolachana, B. S., . . . Weinberger, D. R. (2003). Executive subprocessesin working memory: Relationship to catechol-O-methyltransferaseVal158Met genotype and schizophrenia. Archives of General Psychia-try, 60, 889–896. doi:10.1001/archpsyc.60.9.889

Goldberg, T. E., & Weinberger, D. R. (2004). Genes and the parsing ofcognitive processes. Trends in Cognitive Sciences, 8, 325–335. doi:10.1016/j.tics.2004.05.011

Goldman-Rakic, P. S., Muly 3rd, E. C., & Williams, G. V. (2000). D(1)receptors in prefrontal cells and circuits. Brain Research Reviews, 31,295–301. doi:10.1016/S0165-0173(99)00045-4

Golimbet, V., Gritsenko, I., Alfimova, M., Lebedeva, I., Lezheiko, T.,Abramova, L., & Ebstein, R. (2006). Association study of COMT geneVal158Met polymorphism with auditory P300 and performance on

neurocognitive tests in patients with schizophrenia and their relatives.The World Journal of Biological Psychiatry, 7, 238–245. doi:10.1080/15622970600670970

Golob, E. J., Ringman, J. M., Irimajiri, R., Brightm S., Schaffer, B.,Medina, L. D., & Starr, A. (2009). Cortical event-related potentials inpreclinical familial Alzheimer disease. Neurology, 73, 1649–1655. doi:10.1212/WNL.0b013e3181c1de77

Gray, R., Rajan, A. S., Radcliffe, K. A., Yakehiro, M., & Dani, J. A.(1996). Hippocampal synaptic transmission enhanced by low concen-trations of nicotine. Nature, 383, 713–716. doi:10.1038/383713a0

Hall, M. H., Taylor, G., Sham, P., Schulze, K., Rijsdijk, F., Picchioni, M.,. . . Salisbury, D. F. (2009). The early auditory gamma-band response isheritable and a putative endophenotype of schizophrenia. SchizophreniaBulletin, 37, 778�787.

Herrmann, C. S., Frund, I., & Lenz, D. (2010). Human gamma-bandactivity: A review on cognitive and behavioral correlates and networkmodels. Neuroscience and Biobehavioral Reviews, 34, 981–992. doi:10.1016/j.neubiorev.2009.09.001

Hong, L. E., Summerfelt, A., Mitchell, B. D., McMahon, R. P., Wonodi, I.,Buchanan, R. W., & Thaker, G. K. (2008). Sensory gating endopheno-type based on its neural oscillatory pattern and heritability estimate.Archives of General Psychiatry, 65, 1008 –1016. doi:10.1001/archpsyc.65.9.1008

Hughes, J. R., Hatsukami, D. K., Mitchell, J. E., & Dahlgren, L. A. (1986).Prevalence of smoking among psychiatric outpatients. The AmericanJournal of Psychiatry, 143(8), 993–997.

Kang, C., Xu, X., Liu, H., & Yang, J. (2010). Association study ofcatechol-O-methyltransferase (COMT) gene Val158Met polymorphismwith auditory P300 in Chinese Han patients with schizophrenia. Psychi-atry Research, 180, 153–155. doi:10.1016/j.psychres.2008.07.008

Knight, R. T., Scabini, D., Woods, D. L., & Clayworth, C. C. (1989).Contributions of temporal-parietal junction to the human auditory P3.Brain Research, 502, 109–116. doi:10.1016/0006-8993(89)90466-6

Knott, V. J., & Fisher, D. J. (2007). Naltrexone alteration of the nicotine-induced EEG and mood activation response in tobacco-deprived ciga-rette smokers. Experimental and Clinical Psychopharmacology, 15,368–381. doi:10.1037/1064-1297.15.4.368

Kumari, V., & Postma, P. (2005). Nicotine use in schizophrenia: The selfmedication hypotheses. Neuroscience and Biobehavioral Reviews, 29,1021–1034. doi:10.1016/j.neubiorev.2005.02.006

Kwon, J. S., O’Donnell, B. F., Wallenstein, G. V., Greene, R. W., Hi-rayasu, Y. , Nestor, P. G., . . . McCarley, R. W. (1999). Gammafrequency-range abnormalities to auditory stimulation in schizophrenia.Archives of General Psychiatry, 56, 1001–1005. doi:10.1001/archpsyc.56.11.1001

Lagopoulos, J., Clouston, P., Barhamali, H., Gordon, E., Li, W. M., Lesley,J., & Morris, J. G. L. (1998). Late components of the event-relatedpotentials and their topography in Parkinson’s disease. Movement Dis-orders, 13, 262–267. doi:10.1002/mds.870130211

Lange, K. W., Robbins, T. W., Marsden, C. D., James, M., Owen, A. M.,& Paul, G. M. (1992). L-dopa withdrawal in Parkinson’s disease selec-tively impairs cognitive performance in tests sensitive to frontal lobedysfunction. Psychopharmacology, 107, 394 – 404. doi:10.1007/BF02245167

Lazarewicz, M. T., Ehrlichman, R. S., Maxwell, C. R., Gandal, M. J.,Finkel, L. H., & Siegel, S. J. (2010). Ketamine modulates theta andgamma oscillations. Journal of Cognitive Neuroscience, 22, 1452–1464.doi:10.1162/jocn.2009.21305

Lee, K. H., Williams, L. M., Haig, A., Goldberg, E., & Gordon, E. (2001).An integration of 40 Hz Gamma and phasic arousal: Novelty androutinization processing in schizophrenia. Clinical Neurophysiology,112, 1499–1507. doi:10.1016/S1388-2457(01)00584-3

Leicht, G., Kirsch, V., Giegling, I., Karch, S., Hantschk, I., Möller, H.-J.,. . . Mulert, C. (2010). Reduced early auditory evoked gamma-band

10 CAO ET AL.

response in patients with schizophrenia. Biological Psychiatry, 67, 224–231. doi:10.1016/j.biopsych.2009.07.033

Light, G. A., Hsu, J. L., Hsieh, M. H., Meyer-Gomes, K., Sprock, J.,Swerdlow, N. R., & Braff, D. L. (2006). Gamma band oscillations revealneural network cortical coherence dysfunction in schizophrenia patients.Biological Psychiatry, 60, 1231–1240. doi:10.1016/j.bio-psych.2006.03.055

Lindgren, M., Molander, L., Verbaan, C., Lunell, E., & Rosen, I. (1999).Electroencephalographic effects of intravenous nicotine—a dose-response study. Psychopharmacology, 145, 342–350. doi:10.1007/s002130051067

Loughead, J., Wileyto, E. P., Valdez, J. N., Sanborn, P., Tang, K., Strasser,A. A., . . . Lerman, C. (2009). Effect of abstinence challenge on brainfunction and cognition in smokers differs by COMT genotype. Molec-ular Psychiatry, 14, 820–826. doi:10.1038/mp.2008.132

Lu, C. B., & Henderson, Z. (2010). Nicotine induction of theta frequencyoscillations in rodent hippocampus in vitro. Neuroscience, 166, 84–93.doi:10.1016/j.neuroscience.2009.11.072

Lyon, E. R. (1999). A review of the effects of nicotine on schizophreniaand antipsychotic medications. Psychiatric Services, 50(10), 1346–1350.

Majic, T., Rentzsch, J., Gudlowski, Y., Ehrlich, S., Juckel, G., Sander, T.,. . . Gallinat, J. (2011). COMT Val108/158Met genotype modulateshuman sensory gating. NeuroImage, 55, 818 – 824. doi:10.1016/j.neuroimage.2010.12.031

Matsumoto, M., Weickert, C. S., Beltaifa, S., Kolachana, B., Chen, J.,Hyde, T. M., . . . Kleinman, J. E. (2003). Catechol O-methyltransferase(COMT) mRNA expression in the dorsolateral prefrontal cortex ofpatients with schizophrenia. Neuropsychopharmacology, 28, 1521–1530. doi:10.1038/sj.npp.1300218

Maxwell, C. R., Ehrlichman, R. S., Liang, Y., Gettes, D. R., Evans, D. L.,Kanes, S. J., . . . Siegel, S. J. (2006). Corticosterone modulates auditorygating in mouse. Neuropsychopharmacology: Official Publication of theAmerican College of Neuropsychopharmacology, 31(5), 897–903.

Maxwell, C. R., Ehrlichman, R. S., Liang, Y., Trief, D., Kanes, S. J., Karp,J., & Siegel, S. J. (2006). Ketamine produces lasting disruptions inencoding of sensory stimuli. The Journal of Pharmacology and Exper-imental Therapeutics, 316, 315–324. doi:10.1124/jpet.105.091199

Maxwell, C. R., Liang, Y., Weightman, B. D., Kanes, S. J., Abel, T., Gur,R. E., . . . Siegel, S. J. (2004). Effects of chronic olanzapine andhaloperidol differ on the mouse N1 auditory evoked potential. Neuro-psychopharmacology, 29, 739–746. doi:10.1038/sj.npp.1300376

Mazei, M. S., Pluto, C. P., Kirkbride, B., & Pehek, E. A. (2002). Effects ofcatecholamine uptake blockers in the caudate-putamen and subregionsof the medial prefrontal cortex of the rat. Brain Research, 936, 58–67.doi:10.1016/S0006-8993(02)02542-8

Metzger, K. L., Maxwell, C. R., Liang, Y., & Siegel, S. J. (2007). Effectsof nicotine vary across two auditory evoked potentials in the mouse.Biological Psychiatry, 61, 23–30. doi:10.1016/j.biopsych.2005.12.011

Missonnier, P., Deiber, M. P., Gold, G., Herrmann, F. R., Millet, P.,Michon, A., . . . Giannakopoulos, P. (2007). Working memory load-related electroencephalographic parameters can differentiate progressivefrom stable mild cognitive impairment. Neuroscience, 150, 346–356.doi:10.1016/j.neuroscience.2007.09.009

Monte-Silva, K., Kuo, M. F., Thirugnanasambandam, N., Liebetanz, D.,Paulus, W., & Nitsche, M. A. (2009). Dose-dependent invertedU-shaped effect of dopamine (D2-like) receptor activation on focal andnonfocal plasticity in humans. The Journal of Neuroscience, 29, 6124–6131. doi:10.1523/JNEUROSCI.0728-09.2009

Moron, J. A., Brockington, A., Wise, R. A., Rocha, B. A., & Hope, B. T.(2002). Dopamine uptake through the norepinephrine transporter inbrain regions with low levels of the dopamine transporter: Evidencefrom knock-out mouse lines. Journal of Neuroscience, 22(2), 389–395.

Oram Cardy, J. E., Flagg, E. J., Roberts, W., & Roberts, T. P. (2008).

Auditory evoked fields predict language ability and impairment inchildren. International Journal of Psychophysiology: Official Journal ofthe International Organization of Psychophysiology, 68(2), 170–175.

Owen, A. M., James, M., Leigh, P. N., Summers, B. A., Marsden, C. D.,Quinn, N. P., . . . Robbins, T. W. (1992). Fronto-striatal cognitivedeficits at different stages of Parkinson’s disease. Brain, 115, 1727–1751. doi:10.1093/brain/115.6.1727

Papaleo, F., Crawley, J. N., Song, J., Lipska, B. K., Pickel, J., Weinberger,D. R., & Chen, J. (2008). Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. The Journalof Neuroscience, 28, 8709 – 8723. doi:10.1523/JNEUROSCI.2077-08.2008

Phillips, J. M., Ehrlichman, R. S., & Siegel, S. J. (2007). Mecamylamineblocks nicotine-induced enhancement of the P20 auditory event-relatedpotential and evoked gamma. Neuroscience, 144, 1314–1323. doi:10.1016/j.neuroscience.2006.11.003

Pomerleau, O. F., Downey, K. K., Stelson, F. W., & Pomerleau, C. S.(1995). Cigarette smoking in adult patients diagnosed with attentiondeficit hyperactivity disorder. Journal of Substance Abuse, 7, 373–378.doi:10.1016/0899-3289(95)90030-6

Pontieri, F. E., Tanda, G., Orzi, F., & Di Chiara, G. (1996). Effects ofnicotine on the nucleus accumbens and similarity to those of addictivedrugs. Nature, 382, 255–257. doi:10.1038/382255a0

Ramos-Loyo, J. A., Gonzalez-Garrido, A. A., Sanchez-Loyo, L. M.,Medina, V., & Basar-Eroglu, C. (2009). Event-related potentials andevent-related oscillations during identity and facial emotional processingin schizophrenia. International Journal of Psychophysiology, 71, 84–90.doi:10.1016/j.ijpsycho.2008.07.008

Reuter, M., Peters, K., Schroeter, K., Koebke, W., Lenardon, D., Bloch, B.,& Hennig, J. (2005). The influence of the dopaminergic system oncognitive functioning: A molecular genetic approach. Behavioural BrainResearch, 164, 93–99. doi:10.1016/j.bbr.2005.06.002

Reynolds, G. P., Abdul-Monim, Z., Neill, J. C., & Zhang, Z. J. (2004).Calcium binding protein markers of GABA deficits in schizophrenia—postmortem studies and animal models. Neurotoxicity Research, 6, 57–61. doi:10.1007/BF03033297

Rijsdijk, F. V., Vernon, P. A., & Boomsma, D. I. (1998). The genetic basisof the relation between speed-of-information-processing and IQ. Behav-ioural Brain Research, 95, 77– 84. doi:10.1016/S0166-4328(97)00212-X

Roth, W. T., Pfefferbaum, A., Kelly, A. F., Berger, P. A., & Kopell, B. S.(1981). Auditory event-related potentials in schizophrenia and depres-sion. Psychiatry Research, 4, 199 –212. doi:10.1016/0165-1781(81)90023-8

Rusted, J. M., Sawyer, R., Jones, C., Trawley, S. L., & Marchant, N. L.(2009). Positive effects of nicotine on cognition: The deployment ofattention for prospective memory. Psychopharmacology, 202, 93–102.doi:10.1007/s00213-008-1320-7

Sahai, V., Tandon, O. P., & Sircar, S. S. (2000). Task related changes inERP auditory vs visual tasks. Indian Journal of Physiology and Phar-macology, 44(1), 92–96.

Schmiedt, C., Brand, A., Hildebrandt, H., & Basar-Eroglu, C. (2005).Event-related theta oscillations during working memory tasks in patientswith schizophrenia and healthy controls. Cognitive Brain Research, 25,936–947. doi:10.1016/j.cogbrainres.2005.09.015

Sen, A., Jensen, A. R., Sen, A. K., & Arora, I. (1983). Correlation betweenreaction time and intelligence in psychometrically similar groups inAmerica and India. Applied Research in Mental Retardation, 4, 139–152. doi:10.1016/0270-3092(83)90006-1

Shaikh, M., Hall, M. H., Schulze, K., Dutt, A., Walshe, M., Williams, I.,. . . Bramon, E. (2011). Do COMT, BDNF and NRG1 polymorphismsinfluence P50 sensory gating in psychosis? Psychological Medicine: AJournal of Research in Psychiatry and the Allied Sciences, 41, 263–276.doi:10.1017/S003329170999239X

11NICOTINE NORMALIZES ERPs IN MICE

Sheehan, K. A., McArthur, G. M., & Bishop, D. V. (2005). Is discrimina-tion training necessary to cause changes in the P2 auditory event-relatedbrain potential to speech sounds? Cognitive Brain Research, 25, 547–553. doi:10.1016/j.cogbrainres.2005.08.007

Shenton, M. E., Faux, S. F., McCarley, R. W., Ballinger, R., Coleman, M.,& Duffy, F. H. (1989). Clinical correlations of auditory P200 topographyand left temporo-central deficits in schizophrenia: A preliminary study.Journal of Psychiatric Research, 23, 13–34. doi:10.1016/0022-3956(89)90014-9

Siegel, S. J., Connolly, P., Liang, Y., Lenox, R. H., Gur, R. E., Bilker,W. B., . . . Turetsky, B. I. (2003). Effects of strain, novelty, and NMDAblockade on auditory-evoked potentials in mice. Neuropsychopharma-cology, 28, 675–682. doi:10.1038/sj.npp.1300087

Siegel, S. J., Maxwell, C. R., Majumdar, S., Trief, D. F., Lerman, C., Gur,R. E., . . . Liang, Y. (2005). Monoamine reuptake inhibition and nicotinereceptor antagonism reduce amplitude and gating of auditory evokedpotentials. Neuroscience, 133, 729 –738. doi:10.1016/j.neuroscience.2005.03.027

Sigurdsson, T., Stark, K. L., Karayiorgou, M., Gogos, J. A., & Gordon,J. A. (2010). Impaired hippocampal-prefrontal synchrony in a geneticmouse model of schizophrenia. Nature, 464, 763–767. doi:10.1038/nature08855

Slifstein, M., Kolachana, B., Simpson, E. H., Tabares, P., Cheng, B.,Duvall, M., . . . Abi-Dargham, A. (2008). COMT genotype predictscortical-limbic D1 receptor availability measured with [11C]NNC112and PET. Molecular Psychiatry, 13, 821–827. doi:10.1038/mp.2008.19

Tsai, S. J., Yu, Y. W., Chen, T. J., Chen, J. Y., Liou, Y. J., Chen, M. C.,& Hong, C. J. (2003). Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthyfemales. Neuroscience Letters, 338, 123–126. doi:10.1016/S0304-3940(02)01396-4

Uhlhaas, P. J., & Singer, W. (2010). Abnormal neural oscillations andsynchrony in schizophrenia. Nature Reviews Neuroscience, 11, 100–113. doi:10.1038/nrn2774

Umbricht, D., Vyssotky, D., Latanov, A., Nitsch, R., Brambilla, R.,D’Adamo, P., & Lipp, H. P. (2004). Midlatency auditory event-related

potentials in mice: Comparison to midlatency auditory ERPs in humans.Brain Research, 1019, 189–200. doi:10.1016/j.brainres.2004.05.097

Venables, N. C., Bernat, E. M., & Sponheim, S. R. (2009). Genetic anddisorder-specific aspects of resting state EEG abnormalities in schizo-phrenia. Schizophrenia Bulletin, 35, 826 – 839. doi:10.1093/schbul/sbn021

Verleger, R., Heide, W., Butt, C., & Kömpf, D. (1994). Reduction of P3bin patients with temporo-parietal lesions. Cognitive Brain Research, 2,103–116. doi:10.1016/0926-6410(94)90007-8

Weinberger, D. R., Berman, K. F., & Illowsky, B. P. (1988). Physiologicaldysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A newcohort and evidence for a monoaminergic mechanism. Archives ofGeneral Psychiatry, 45, 609 – 615. doi:10.1001/archpsyc.1988.01800310013001

Williams, L. M., Gordon, E., Wright, J., & Bahramali, H. (2000). Latecomponent ERPs are associated with three syndromes in schizophrenia.International Journal of Neuroscience, 105, 37–52. doi:10.3109/00207450009003264

Williams-Gray, C. H., Hampshire, A., Robbins, T. W., Owen, A. M., &Barker, R. A. (2007). Catechol O-methyltransferase Val158Met geno-type influences frontoparietal activity during planning in patients withParkinson’s disease. The Journal of Neuroscience, 27, 4832–4838.doi:10.1523/JNEUROSCI.0774-07.2007

Wright, M. J., Luciano, M., Hansell, N. K., Geffen, G. M., Geffen, L. B.,& Martin, N. G. (2002). Genetic sources of covariation among P3(00)and online performance variables in a delayed-response working mem-ory task. Biological Psychology, 61, 183–202. doi:10.1016/S0301-0511(02)00058-3

Yue, C., Wu, T., Deng, W., Wang, G., & Sun, X. (2009). Comparison ofvisual evoked-related potentials in healthy young adults of differentcatechol-O-methyltransferase genotypes in a continuous 3-back task.NeuroReport: For Rapid Communication of Neuroscience Research, 20,521–524. doi:10.1097/WNR.0b013e328317f3b1

Received September 11, 2011Revision received November 15, 2011

Accepted December 6, 2011 �

12 CAO ET AL.