Schizophrenia Research 128 (2011) 171–172
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Schizophrenia Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Letter to the Editor
Spatial working memory impairments induced by
cigarette smoking abstinence are correlated with plasma
nicotine levels in schizophrenia
Dear Editors,
It is thought that the high rates of smoking in schizophre-
nia (55–88%) may be due in part to nicotine's ability to
improve select cognitive deficits associated with this disorder
(George et al., 2002; Sacco et al., 2005). A human laboratory
study conducted by Sacco et al. (2005) examined the effects
of cigarette smoking on cognitive function in smokers with
schizophrenia, in comparison to controls, and the involve-
ment of nicotinic acetylcholine receptor (nAChR) mechan-
isms. Overnight abstinence from smoking impaired Hit Rate
on the Continuous Performance Test (CPT), a measure of
sustained attention, in both groups; while visuospatial
working memory (VSWM) at the 30 s delay was only
impaired in smokers with schizophrenia. Reinstatement of
smoking reversed abstinence induced cognitive impairments.
The non-selective nAChR antagonist mecamylamine hydro-
chloride (Inversine®; MEC) selectively blocked the enhance-
ment of VSWM and CPT performance by smoking
reinstatement in schizophrenia participants, suggesting that
these effects depend on nAChR stimulation. The present study
sought to examine the relationship between the pro-
cognitive effects of cigarette smoking and levels of circulating
plasma (and brain) nicotine.
A secondary analysis of data collected in Sacco et al.'s
(2005) study was conducted using a subset of schizophrenia
(n = 22) and control smokers (n = 22) who had complete
neurocognitive and nicotine level data. A detailed description
of subject demographics and study procedures can be found
in the original manuscript (Sacco et al., 2005). Three
consecutive test weeks examined the effect of 3 days of
MEC treatment (0, 5 or 10 mg/day) on neurocognitive
function assessed on day 2 (baseline smoking), day 3 AM
(following overnight abstinence) and day 3 PM (following
smoking reinstatement). The relationships between changes
in nicotine levels and cognitive performance produced by
smoking abstinence and reinstatement were examined by
partial correlation analyses (controlling for age).
In smokers with schizophrenia, the impairment in VSWM
following overnight abstinence was positively correlated
with baseline plasma nicotine levels in the MEC placebo
condition (0.0 mg/day) (r = 0.45, p = 0.04) and the decrease
in levels following abstinence (r = 0.48, p = 0.03; Fig. 1A).
0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2010.10.011
MEC pre-treatment at 5.0 mg/day abolished this positive
correlation between the decrease in plasma nicotine levels
and VSWM impairment (r = − 0.55, p = 0.01; Fig. 1A);
Fischer r-to-z transformations demonstrated that the corre-
lation coefficients at 0 and 5 mg/day MEC were significantly
different (p b 0.01). At 10 mg/day, MEC produced impairment
of baseline cognitive function in smokers with schizophrenia
and there was no correlation between VSWM impairment
and nicotine levels (r = 0.15, p = 0.51). The improvement in
VSWM and increase in nicotine levels produced by smoking
reinstatement were not correlated (r = 0.16, p = 0.54). In
control smokers, VSWM was not correlated with changes in
plasma nicotine levels following smoking abstinence (r =
− 0.03, p = 0.89; Fig. 1B) or reinstatement (r = − 0.38,
p = 0.21). There were no correlations between nicotine levels
and CPT Hit Rate in either group.
These analyses suggest that in schizophrenia, the magni-
tude of spatial working memory impairment produced by
overnight abstinence is strongly related to nicotine intake
(i.e., the greater the level of nicotine intake and therefore
greater reduction in abstinence, the greater the degree of
cognitive deficit observed). Given that VSWM is dependent
on prefrontal cortical dopamine (DA) function and that
nicotine withdrawal is associated with reductions in DA
function, these data suggest that changes in VSWM as a
function of abstinence are related to nicotine-induced
changes in prefrontal cortical DA functions. This is particu-
larly relevant to smokers with schizophrenia as they extract
more nicotine per cigarette than smokers without a psychi-
atric illness (Olincy et al., 1997; Sacco et al., 2005), possibly in
an attempt to remedy nAChR-related prefrontal DA deficits
(Breese et al., 2000; George, 2007).
MEC disrupted this relationship despite having no effect
on nicotine levels; no such effects were observed in control
smokers. We believe that this finding provides further
evidence to support the role central nAChRs play in
modulating the pro-cognitive effects of cigarette smoking in
schizophrenia. In contrast, the improvement in VSWM
produced by smoking reinstatement appears not to be related
to plasma nicotine levels. One explanation for this finding is
that differences in the state of nAChRs (Picciotto et al., 2008)
at the baseline (i.e., desensitized due to smoking satiation)
and reinstatement (i.e., resensitized due to overnight absti-
nence) lead to differential relationships between nicotine
levels and cognitive performance.
Performance on the CPT was not correlated with nicotine
levels. Similarly differential effects of MEC on VSWM and the
CPT have been reported (Sacco et al., 2005). It is possible that
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Fig. 1. Scatter plots demonstrating the relationship between plasma nicotine levels (ng/ml) and percentage change in VSWM-30 performance following overnight
smoking abstinence in schizophrenia (A) and control (B) smokers at MEC doses of 0 mg/day (represented by circles) and 5 mg/day (represented by squares).
the performance-enhancing effects of cigarette smoking on
VSWM and sustained attention are modulated by different
mechanisms such as disparate nAChR subtypes (e.g. α4β2
versus α7), and associated neurotransmitter systems.
Tobacco treatment studies indicate that cognitive deficits,
particularly those related to prefrontal function, such as
VSWM, predict smoking cessation failure in schizophrenia
(Dolan et al., 2004; Moss et al., 2009). The results of this study
suggest that smokers with schizophrenia who have higher
nicotine levels and therefore suffer greater impairment in
VSWM upon quitting may be at particular risk for relapse and
thus might benefit from targeted treatment strategies, such as
medications which augment prefrontal dopaminergic func-
tion (e.g. Sacco et al., 2009).
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Letter to the Editor
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Victoria C. Wing
Department of Psychiatry, University of Toronto and the Centre
for Addiction and Mental Health, Toronto, ON, Canada
Corresponding author. Centre for Addiction and Mental Health,
33 Russell St, Toronto, ON, M5S 2S1, Canada.
Tel.: +1 416 535 8501x4882; fax: +1 416 979 4676.
E-mail address: vicky_wing@camh.net.
Kristi A. Sacco
Division of Substance Abuse, Department of Psychiatry,
Yale University School of Medicine,
Connecticut Mental Health Center, New Haven, CT, USA
Tony P. George
Department of Psychiatry, University of Toronto and the Centre
for Addiction and Mental Health, Toronto, ON, Canada
Division of Substance Abuse, Department of Psychiatry,
Yale University School of Medicine,
Connecticut Mental Health Center, New Haven, CT, USA
30 April 2010