1. Behavioral Neuroscience
Nicotine Normalizes Event Related Potentials in
COMT-Val-tg Mice and Increases Gamma and Theta
Spectral Density
Yufei A. Cao, Robert E. Featherstone, Michael J. Gandal, Yuling Liang, Catherine Jutzeler, John
Saunders, Valerie Tatard-Leitman, Jingshan Chen, Daniel R. Weinberger, Caryn Lerman, and
Steven J. Siegel
Online First Publication, February 6, 2012. doi: 10.1037/a0027047
CITATION
Cao, 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, February
6). Nicotine Normalizes Event Related Potentials in COMT-Val-tg Mice and Increases Gamma
and Theta Spectral Density. Behavioral Neuroscience. Advance online publication. doi:
10.1037/a0027047
3. COMT is particularly important in regions such as the prefrontal
cortex, where the density of dopamine transporters is relatively
low (Mazei, Pluto, Kirkbride, & Pehek, 2002; Moro´n, Brocking-
ton, Wise, Rocha, & Hope, 2002; Matsumoto et al., 2003). COMT
contains a common, functional sequence variation in a single
nucleotide polymorphism that results in a valine to methionine
substitution at codon 158. This leads to upward of a twofold
increase in enzymatic activity and dopamine catabolism, thereby
significantly reducing basal dopamine levels in COMT-Val carriers
(Chen et al., 2004).
A genetic association between COMT and schizophrenia has
been observed in a number of studies, but the association is
statistically 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 in
normal subjects and in patients with schizophrenia. Studies have
suggested that working memory deficits characteristic of patients
with schizophrenia are also heritable and associated with suscep-
tibility to the disease (Goldberg et al., 2003). In a study by Egan
et 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 allele
demonstrating worse cognitive performance. Similarly, executive
function is significantly altered by COMT genotype in patients
with Parkinson’s disease and depression. However, the genotype-
Ϫphenotype relationship is reversed in Parkinson’s disease such
that the high-activity allele confers a cognitive advantage (Foltynie
et al., 2004; Williams-Gray et al., 2007). Because catecholamine
dysfunction is involved in various neurological disorders, the
COMT enzyme and gene provide potential targets for pharmaco-
logical treatments.
In addition to displaying cognitive impairments, patients with
several psychiatric disorders often exhibit an increased tendency to
smoke tobacco (Pomerleau, Downey, Stelson, & Pomerleau, 1995;
Esterberg, Jones, Compton, & Walker, 2007). This is especially
true 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 increase
in smoking frequency are not well understood, studies have sug-
gested that nicotine may improve cognitive functions that are
critically affected in schizophrenia, such as attention and working
memory (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 and
without schizophrenia, carriers of the COMT-Val allele are more
likely to develop nicotine dependence and be less responsive to
nicotine replacement therapy (Addington, el-Guebaly, Addington,
& Hodgins, 1997; George et al., 2000; George et al., 2002; Colilla
et al., 2005; Beuten, Payne, Ma, & Li, 2006). Moreover, smokers
with the COMT-Val/Val genotype are more prone to nicotine
abstinence-induced cognitive deficits and decreased prefrontal ac-
tivity during performance of working memory tasks (Loughead et
al., 2009). Because nicotine stimulates the release of cortical
dopamine, this may counteract the excessive dopamine inactiva-
tion by the high-activity COMT-Val variant. Thus, nicotine is
suggested to reestablish a more optimal dopaminergic balance by
potentiating dopamine release, thereby attenuating cognitive def-
icits (Pontieri, Tanda, Orzi, & Di Chiara, 1996; Lyon, 1999).
Cognitive impairments have been associated with changes in
neural oscillations, which in turn are also associated with ge-
netic polymorphisms in the dopamine pathway (Venables, Ber-
nat, & Sponheim, 2009). Additionally, electrophysiological
studies have indicated that gamma and theta oscillations medi-
ate cognitive processes in mammalian brains (Herrmann, Fru¨nd,
& Lenz, 2010). Growing evidence has indicated that oscillatory
brain activity is disturbed in patients of schizophrenia. In par-
ticular, reduced evoked power as well as impaired synchrony in
the theta and gamma frequency ranges have been consistently
reported (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 the
human 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 P80
components of the auditory event-related potential (ERP), as
well as on baseline and auditory event-related power and phase
synchrony in theta and gamma frequency ranges. We also
examined 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. We
tested the following hypotheses:
1. COMT-Val-tg mice will manifest a reduction in the am-
plitude of ERP components that have been associated
with cognitive function, including the P80, which is the
mouse analog of the human P200 (Umbricht et al., 2004).
2. The high-activity COMT-Val-tg mice will have increased
P80 ERP latency, similar to humans with the high-
Figure 1. Graphic representation of proposed inverted-U relationship
between dopamine neurotransmission and cognitive efficiency. Note that
nicotine is proposed to move organisms with the high-activity COMT-Val
allele to a more optimal level of function by restoring optimal dopamine
availability. WT ϭ wild-type.
2 CAO ET AL.
4. activity Val allele, and patients with schizophrenia, Par-
kinson’s disease, mild cognitive impairment, and familial
Alzheimer’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 activity
in a manner consistent with its effects on cognition in
humans (Bramon et al., 2006; Cooray, Maurex, & Bris-
mar, 2008). Specifically, we anticipated a reduction theta,
without changes in gamma activity among COMT-Val
subjects, as previously found in human clinical studies
(Demiralp et al., 2007; Venables et al., 2009).
4. Nicotine will increase amplitude of the P20, decrease
amplitude 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 reduction
in 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 gamma
and theta time-frequency measures.
Method
Animals
The COMT-Val-tg mice were obtained from the intramural
program at the National Institute of Mental Health, and a breeding
colony was established at the University of Pennsylvania. COMT-
Val transgenic mice were crossbred with neuron-specific enolase
(NSE)-tetracycline transactivator (tTA) transgenic mice to bring
the COMT-Val and tTA transgenes together and achieve tissue-
specific expression. Single transgenic COMT-Val mice, NSE-tTA
mice, and mice carrying neither transgene were pooled together in
the control group as previously described (Papaleo et al., 2008).
Mice were identified by polymerase chain reaction analysis of tail
DNA. Animals were maintained on a 12-h lightϪdark cycle in a
temperature-controlled facility with food and water available ad
libitum. Mice were housed four to five per cage and acclimated to
the 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 42
animals were used as follows: nine transgenic females, 10 trans-
genic males, 11 wild-type littermate females, and 10 wild-type
littermate males.
Electrode Implantation
Animals were anesthetized with isofluorane prior to and during
electrode implantation. Differential (positive, negative, and
ground) recording electrodes (Plastic One Inc.) were stereotaxi-
cally implanted in the right CA3 region of the hippocampus (1.8
mm posterior, 2.65 mm lateral, and 2.75 mm deep relative to the
bregma) 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 animals
were allowed to recover for at least 1 week prior to recording. All
procedures 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 the
home cage environment placed in a Faraday cage. Auditory
stimuli were generated by Micro1401 hardware and Spike2,
version 6.0 software (Cambridge Electronic Design) and were
delivered 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 for
the first, baseline, trial. Animals then received a 0.1-ml intra-
peritoneal injection of 0.09% saline 5 min prior to stimulus
onset during the second trial. Animals then received a 0.1-ml
intraperitoneal injection of nicotine hydrogen tartrate salt
(Sigma-Aldrich) dissolved in 0.09% saline at a dose of 0.5
mg/kg 5 min prior to stimulus onset during the third trial. The
dose of nicotine was chosen based on previous studies (Siegel
et al., 2005; Metzger et al., 2007; Phillips et al., 2007). The
stimulus protocol consisted of 50 paired white-noise bursts
(10-ms duration, 500-ms intrapair interval) with a 9-s interpair
interval presented at 85 dB compared to a 70-dB white-noise
background. Individual ERP waveforms were sampled at 1667
Hz, filtered between 1 and 500 Hz, and rejected for movement
artifact based on the criterion of two times the root mean
squared amplitude per mouse. Average waveforms for individ-
ual mice were baseline corrected at 0 ms poststimulus. Grand
average waves were then produced from 0 to 300 ms after
stimulus onset.
Electroencephalographic Data Analysis
ERP amplitude and latency. The amplitudes and latencies
of three auditory-evoked potential components were calculated
following the response to the first stimulus for each mouse at
baseline, postsaline, and postnicotine (0.5 mg/kg) (see Figure
2). The first component, the P20, is a positive deflection be-
tween 15 and 35 ms, and is proposed to be the mouse analog of
the human P50 (Connolly et al., 2003; Siegel et al., 2003). The
second component, named the N40, is defined as the trough
between 25 and 60 ms, similar to the human N100 (Maxwell et
al., 2004). A third component, termed the P80, is defined as a
positive deflection between 60 and 300 ms directly after the
N40 and displays response properties similar to the human P200
(Siegel et al., 2003). The amplitudes of the P20 and P80
components of the ERP waveform were chosen by determining
the maximum positive deflection between 15 and 35 ms and
between 60 and 300 ms, respectively. The amplitude of the N40
component was chosen by determining the maximum negative
deflection 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) was
performed on baseline- and artifact-corrected data for the am-
3NICOTINE NORMALIZES ERPs IN MICE
5. plitude of each ERP component to identify interactions between
stimulus, genotype, sex, and treatment condition, as well as
main effects. Similarly, ANOVAs were performed on data for
latency of each component to identify interactions between
nicotine and genotype and sex, and main effects. All data
analyses were performed using Statistica, version 6.1 (StatSoft
Inc.) with significance set at p Ͻ .05.
Time-frequency analysis. Spectral decomposition of
auditory-evoked response waveforms was performed using the
EEGLAB toolbox in Matlab, as published (Delorme & Makeig,
2004; Gandal et al., 2010). Single-trial epochs between Ϫ0.3
and 0.8 s relative to the first stimulus (S1) were extracted from
the continuous electroencephalographic data sampled at 1667
Hz. 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 100
Hz, 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 (Ϫ200 to 0 ms) in each fre-
quency band. PLF is expressed as a unitless ratio between 0 and
1, where 1 represents complete phase synchrony at a given
frequency 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 baseline
power 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 as
a grand average of all traces (b). P20, N40, and P80 are noted.
4 CAO ET AL.
6. 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 ϫ Sex ϫ Drug ϫ Frequency
ANOVA. Significant interactions were followed by Fisher’s least
significant 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 P20
amplitude and latency, with nicotine resulting in both a greater P20
amplitude and a longer P20 latency compared with controls (p ϭ
.029, p Ͻ .001; Figure 3) (Metzger et al., 2007; Amann, Phillips,
Halene, & Siegel, 2008). There was also an effect of sex for the
P20 amplitude, which approached statistical significance (p ϭ
.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 ϭ .069), with the COMT-
Val-tg mice revealing a longer P20 latency compared with their
wild-type littermates. There were no significant interactions be-
tween genotype and treatment, or sex and treatment for either P20
amplitude or latency.
N40 amplitude and latency. There were significant main
effects of nicotine on N40 amplitude (p Ͻ .001) and latency (p ϭ
.018), with nicotine attenuating N40 amplitude and increasing N40
latency, consistent with previously published data (Phillips et al.,
2007; Amann et al., 2008). There was also a significant effect of
genotype on N40 latency (p ϭ .039; Figure 4), with the COMT-
Val-tg mice exhibiting longer N40 latency than their wild-type
littermates. 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 amplitude
revealed a significant effect of genotype (p Ͻ .003), with wild-
type mice exhibiting greater P80 amplitude than the COMT-Val-tg
mice. There was also a significant main effect of nicotine on this
measure (p Ͻ .001). There was no significant interaction between
genotype and treatment condition (p ϭ .602). Of note, nicotine
increased P80 amplitude of the COMT-Val-tg mice to match the
level of wild-type littermates on saline treatment (see Figure 5).
The COMT-Val-tg mice demonstrated qualitatively longer P80
latency than their wild-type littermates, although the difference
was not significant (data not shown). Analysis of P80 latency also
revealed a significant main effect of nicotine on P80 latency, with
baseline and saline-treated animals displaying a longer P80 latency
than nicotine treated (p Ͻ .001; see Figure 2a).
Electroencephalographic Time-Frequency Analyses
Theta and gamma spectral power. Time-frequency plots for
each condition are shown in Figure 6. ANOVA revealed a signif-
icant genotype effect on baseline power in the theta and gamma
frequency ranges, with the COMT-Val-tg mice exhibiting lower
total power than their wild-type littermates (theta: p ϭ .042,
gamma: p ϭ .034; Figure 7). Furthermore, there was a significant
reduction in baseline power postnicotine in the theta and gamma
bands, in both groups of mice (p Ͻ .001 for both frequency
ranges). No sex or interaction effects were observed.
No genotype or sex effect was observed for poststimulus power.
However, nicotine significantly increased auditory-evoked power
in the theta and gamma frequency ranges in the COMT-Val-tg
mice and the wild-type littermates (p Ͻ .001; Figure 8a, b). No
interactions among gene, sex, and nicotine conditions were ob-
served.
Theta and gamma phase synchrony. No genotype or sex
effects were observed for PLF (i.e., intertrial coherence). Similar
to evoked power, nicotine significantly increased PLF in the theta
and gamma ranges in COMT-Val-tg and wild-type mice (theta
PLF: p Ͻ .01, gamma PLF: p Ͻ .001, see Figure 8c, d). There were
no main effects or interactions involving sex for any measure of
oscillatory activity.
Discussion
This study examined the effects of nicotine treatment on
electroencephalographic-related outcome measures in COMT-
Val-tg mice and their wild-type littermates. The effects of nicotine
included an increase in P20 and P80 amplitudes, a decrease in N40
amplitude, a lengthening of P20 and N40 latencies, and a reduction
in 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 amplitudes
and latencies. Nicotine increased P20 and N40 latencies, and decreased
P80 latency relative to saline control injections. There was no significant
difference between baseline (no injection) and saline injections (a). Nico-
tine increased P20 and P80, while decreasing N40 amplitude (b). Error bars
represent standard error of the mean, ء
p Ͻ .05. ءءء
p Ͻ .001.
5NICOTINE NORMALIZES ERPs IN MICE
7. chrony (PLF), yielding an increase in signal-to-noise ratio across
theta and gamma frequency ranges.
The current data in mice are consistent with previous studies in
humans that have examined the association of COMT genotype
with ERP measures. Although no data are available on the effects
of COMT polymorphisms on P50 or N100 amplitude or latency,
previous studies have shown that COMT-Val/Met genotype does
not alter P50 gating, consistent with the lack of change in P20
presently 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/Met
and Val/Val individuals (Majic et al., 2011). Previous studies have
also suggested that COMT activity is associated with task-related
P300 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 latency
obligatory ERPs, including the P200, that are independent of task
performance. Data in the current study suggest that COMT activity
has 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 corresponding
alterations in human disorders that are thought to involve altera-
tions of dopamine neurotransmission. Specifically, clinical studies
have demonstrated decreased P200 amplitude in patients with
schizophrenia, 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 thought
to contribute to cognitive dysfunction, especially deficits in exec-
utive function, working memory, planning, and attentional set
shifting (Lange et al., 1992; Owen et al., 1992). Modern treatments
used 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 a
precursor of dopamine synthesis; and COMT inhibitors, such as
tolcapone, to prevent dopamine metabolism. Indeed, tolcapone has
been 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 alleviates
cognitive deficits. Similarly, medications that inhibit dopamine
reuptake, such as bupropion, have been shown to be efficacious in
both depression and smoking cessation. This suggests an associa-
tion of psychiatric disorders and nicotine dependence with a
dopamine-dependent endophenotype involving suboptimal cortical
dopamine 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 dopamine
at D1 receptors in the prefrontal cortex (Slifstein et al., 2008).
Clinical studies have also demonstrated reduced P200 amplitude in
patients with schizophrenia, consistent with data in patients with
depression and Parkinson’s disease (Roth et al., 1981; Shenton et
al., 1989; Lagopoulos et al., 1998; Williams et al., 2000). These
data implicate an association between reduced cortical dopamine
and 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 the
current study, we observed lower P80 amplitude in COMT-Val-tg
mice, compared to their wild-type littermates. We also observed
increases in P80 amplitude in response to nicotine in both groups,
consistent with previous data on the effects of nicotine on ERP
component amplitudes (Amann et al., 2008). Although there was
no 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 the
COMT-Val-tg group after nicotine administration was similar to
the 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 that
nicotine reestablishes normal dopaminergic balance in individuals
with the high-activity allele (Lyon, 1999). The effects of nicotine
on P80 presumably functions by the aforementioned mechanism,
by potentiating cortical dopamine levels. Conversely, nicotine’s
effects on P80 in the wild-type littermates may be disadvantageous
Figure 4. Analysis of COMT-Val-tg on N40 latency. The COMT-Val-tg
mice exhibited longer N40 latency across the three treatment conditions.
Data are presented as mean Ϯ standard error of the mean. WT ϭ wild-type.
ء
p Ͻ .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 all
three treatment conditions. However, nicotine increased P80 amplitude of
the COMT-Val-tg mice to a level comparable to that of control littermates
in the prenicotine conditions. WT ϭ wild-type. ءء
p Ͻ .01. ءءء
p Ͻ .001.
6 CAO ET AL.
8. with respect to the proposed inverted-U relationship between do-
pamine levels and cognition.
ERP component latency has been used as a surrogate marker of
processing speed, and previous data has suggested that increasing
latency represents a deficit in neural processing efficiency (Oram
Cardy, Flagg, Roberts, & Roberts, 2008). Numerous studies have
demonstrated that processing speed correlates directly with IQ
scores 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 either
saline (SAL) or nicotine (NIC). Power is expressed in decibels, as shown in the upper right corner. WT ϭ
wild-type.
Figure 7. Analysis of the effects of COMT-Val-tg on total power. COMT-Val-tg mice exhibit lower baseline
power than their wild-type (WT) littermates for theta and gamma power (a). There was also a significant
reduction in baseline power postnicotine in the theta (b) and gamma (c) ranges across both groups of mice. ء
p Ͻ
.05. ءءء
p Ͻ .001.
7NICOTINE NORMALIZES ERPs IN MICE
9. don, & Sircar, 2000; Wright et al., 2002). Because the
temporalϪparietal cortex is one of the primary generators of both
P300 and P200, several studies have suggested that shortened P200
latency 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 was
not significant. Further, the P80 latency of both groups was re-
duced in response to nicotine, which was more pronounced for the
COMT-Val-tg group. These data suggest a potential mechanism for
improvement 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 COMT
activity across cortical potentials.
Neural synchrony has recently emerged as an important feature
of brain activity in the study of schizophrenia. Measures of theta
and 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 with
schizophrenia and is associated with memory deficits seen in the
illness (Davalos, Kisley, Polk, & Ross, 2003; Schmiedt, Brandl,
Hildebrandt, & Basar-Eroglu, 2005; Brockhaus-Dumke, Mueller,
Faigle, & Klosterkoetter, 2008; Ramos-Loyo, Gonza´lez-Garrido,
Sa´nchez-Loyo, Medina, & Basar-Eroglu, 2009). Additionally, re-
duced gamma power is thought to underlie the types of sensory
processing and cognitive deficits that are common among people
with 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 oscillatory
measures, a few studies have investigated the direct effects of the
COMT genotype on theta and gamma power. One study has shown
that 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 across
trials that is independent of oscillatory amplitude and therefore is
a direct measure of neural synchronization. Clinical studies of
schizophrenia have described disrupted neural synchrony, consis-
tent with data from a genetic mouse model of schizophrenia that
showed a reduction in phase-locking after microdeletion of a
schizophrenia 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 no
significant 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 and
the previous one, which could limit the direct comparison of
results. Nevertheless, this suggests that changes in COMT alone
are 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, we
also evaluated changes in spectral response to nicotine. Nicotine
has been shown to reduce baseline theta power, consistent with our
findings in the present study (Lindgren, Molander, Verbaan,
Lunell, & Rose´n, 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 gamma
power, 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 of
tasks and measures related to attention and memory, presumably
by potentiating cortical dopamine release (Froeliger, Gilbert, &
McClernon, 2009; Rusted, Sawyer, Jones, Trawley, & Marchant,
2009). Alternatively, there was no effect of COMT-Val-tg on this
relationship in the current study, suggesting that the effect of
nicotine 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 the
effects of each on dopamine release and metabolism. Although
dopamine likely plays a key role in observed changes in ERPs and
theta 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 suggested
that both glutamate and gamma-aminobutyric acid (GABA) sys-
tems are involved in the generation and modulation of ERPs and
high (gamma) and low (theta) frequency oscillations. Multiple
studies have implicated dopamine and other monoamines, such as
serotonin and norepinephrine, as well as GABA, glutamate, and
stress 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 et
al., 2009; Bodarky et al., 2009; Gandal et al., 2010). Additional
studies in mice have suggested that alterations in glutamate and
GABA 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 ϭ event-related spectral perturbation. ءء
p Ͻ .01. ءءء
p Ͻ .001.
8 CAO ET AL.
10. 2010; Belforte et al., 2010; Gandal et al., 2011). Consistent with
these findings, alterations in GABA cell populations that contain a
relatively high proportion of glutamate receptors have been dem-
onstrated in postmortem brains of patients with schizophrenia, who
exhibited a pattern of increased resting and decreased evoked
gamma 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 the
complex interaction of multiple neurotransmitter systems.
Conclusion
The current study demonstrates that COMT activity specifically
alters 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 among
people with the high-activity allele. Similarly, nicotine increased
the 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 impaired
brain activity. These findings may have implications for the treat-
ment of nicotine dependence in high-risk smokers who carry the
COMT-Val allele.
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Received September 11, 2011
Revision received November 15, 2011
Accepted December 6, 2011 Ⅲ
12 CAO ET AL.
