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Effects of Long-term Cigarette Smoking on the Human Locus Coeruleus
Violetta Klimek, PhD;
Meng-Yang Zhu, MD, PhD;
Ginny Dilley, BS;
Lisa Konick, BS;
James C. Overholser, PhD;
Herbert Y. Meltzer, MD;
Warren L. May, PhD;
Craig A. Stockmeier, PhD;
Gregory A. Ordway, PhD
Arch Gen Psychiatry. 2001;58:821-827.
ABSTRACT
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Background It has been hypothesized that cigarette smoking among subjects with
major depression is a form of self-medication. To explore a possible biological
basis for this hypothesis, noradrenergic proteins in the locus coeruleus (LC)
were measured in long-term cigarette smokers and in nonsmokers. The LC was
studied because elevated amounts of  2-adrenoceptors and
tyrosine hydroxylase have been observed postmortem in the LCs of subjects
with major depression or who commit suicide, and because long-term administration
of antidepressant drugs to rats down-regulates these proteins in the LC.
Methods Postmortem LCs were obtained from long-term cigarette smokers (n=7)
and from nonsmokers (n = 9), all of whom lacked diagnoses of major depression.
Amounts of tyrosine hydroxylase immunoreactivity and radioligand binding to
the norepinephrine transporter, monoamine oxidase A, and 2-adrenoceptors
were measured.
Results Amounts of tyrosine hydroxylase immunoreactivity and radioligand binding
to 2-adrenoceptors were significantly lower (approximately
60% and 40%, respectively) along the axis of the LCs of long-term smokers
compared with nonsmokers. Smoking had no statistically significant effects
on binding to monoamine oxidase A or to the norepinephrine transporter.
Conclusion This is the first demonstration that cigarette smoking affects noradrenergic
proteins in the LC. The direction of these changes is opposite to that observed
when comparing subjects who have major depression with normal controls and
the same as that produced by long-term antidepressant treatment in animals.
If the present observations reflect long-term effects of smoking on premortem
noradrenergic biochemistry, smoking-induced changes in LC biochemistry may
strengthen the smoking habit among subjects with major depression.
INTRODUCTION
THE HIGH prevalence of cigarette smoking in persons with depression1, 2 and difficulties with successful smoking
cessation among depressed patients has led researchers to hypothesize that
smoking is a type of self-medication. In a study involving 3200 community
residents,3 among individuals with a history
of major depression, 65% of the women and 80% of the men were regular smokers.
Moreover, among those with a lifetime history of major depression, less than
14% of smokers were able to stop smoking and remain abstinent. Another study
of 3023 individuals from the National Health and Nutrition Examination Survey
also demonstrated a higher rate of smoking and a lower rate of smoking cessation
with increasing levels of depression.4 Two
biological actions of components of smoke provide further support for the
self-medication hypothesis. Cigarette smoke contains a substance that inhibits
monoamine oxidase (MAO).5, 6 It
also contains nicotine, which is an agonist at nicotinic receptors.7 Interestingly, MAO inhibitors are effective antidepressants,
and a recent study demonstrates antidepressant-like properties of nicotinic
agonists in a rat behavioral model.8, 9
If tobacco has antidepressant properties, smoking might correct neurochemical
deficits associated with depression; that is, the effects of smoking on brain
biology might be similar to the effects of antidepressant drugs. Antidepressant
drugs have profound effects on the neurochemistry of the noradrenergic locus
coeruleus (LC). Long-term treatment of rats with antidepressant drugs of a
variety of chemical and/or pharmacological classes down-regulates tyrosine
hydroxylase in the LC.10 In contrast, repeated
treatment of rats with psychoactive compounds lacking antidepressant activity
does not affect LC tyrosine hydroxylase. Radioligand binding to 2-adrenoceptors is also reduced in the rat LC following repeated antidepressant
drug treatment.11 These biological effects
of antidepressants may be important for therapeutic efficacy because elevated
levels of tyrosine hydroxylase12 and increased
radioligand binding to 2-adrenoceptors13
have been observed in the postmortem LCs of subjects diagnosed as having major
depression, compared with psychiatrically healthy control subjects.
Because certain actions of the components of cigarette smoke resemble
those of antidepressant drugs, the present study examined the possibility
that long-term cigarette smoking might produce lower tyrosine hydroxylase
and decreased 2-adrenoceptor binding in the human LC, similar
to the effects of repeated antidepressant drug treatment on rats. Therefore,
amounts of noradrenergic proteins in the LCs of subjects with a history of
chronic smoking and of nonsmokers were compared.
SUBJECTS AND METHODS
Human brain tissue was obtained at autopsy at the Cuyahoga County coroner's
office in Cleveland, Ohio, in accordance with an approved institutional review
board protocol. Cadavers were refrigerated on arrival at the coroner's office
and coded to protect identities. Causes of death were determined by the coroner
(Table 1). Information on the
lifetime and current (within the last month) psychiatric status, use of psychotropic
medication, and illicit drug use of all subjects was obtained in structured
clinical interviews14, 15 with
the next of kin. This information was used to identify smokers and to exclude
a principal psychiatric diagnosis of major depression or schizophrenia. The
interview used was the Schedule for Affective Disorders and Schizophrenia,
Lifetime Version,16 supplemented with questions
from the Diagnostic Interview Schedule17 to
make diagnoses compatible with the DSM-III-R.18 Evaluation of drug and alcohol abuse and dependency
was assessed using the Diagnostic Interview Schedule. Axis I diagnoses were
made by a psychiatrist (H.Y.M.) and a clinical psychologist (J.C.O.) based
on data gathered from the structured interview and, when available, hospital
and physician's records. A toxicology screen of blood, bile, and urine from
all of the subjects was performed by the Cuyahoga County coroner's office
as described previously.19, 20
Qualitative and quantitative assays were used to detect the following compounds
or classes of compounds: ethanol, barbiturates, benzodiazepines, sympathomimetic
drugs, and many antidepressant and antipsychotic drugs and their metabolites.
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Table 1. Psychiatric Information on Study Subjects Obtained Through
Psychiatric Autopsy*
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Information on smoking history was also collected in the interview (Table 1). Smokers were defined as people
who smoked 20 or more cigarettes daily up until the time of death; nonsmokers
were people with no history of cigarette smoking or tobacco chewing. Questions
provided information about whether the subject was a cigarette smoker or chewing-tobacco
user at the time of death, whether the subject had a history of smoking or
chewing, whether the subject was exposed to secondhand smoke (including the
nature and extent), the number of years since the subject had quit smoking
or chewing (if a quitter), the number of cigarettes smoked per day, and the
number of years that the individual smoked cigarettes or chewed tobacco.
Postmortem brain tissue samples containing the LC were obtained from
7 smokers and 9 nonsmokers (Table 1).
One smoking and one nonsmoking subject had an adjustment disorder with depressed
mood, and both had died of suicide. No other smoking or nonsmoking subjects
had major psychiatric diagnoses. Ages ranged from 26 to 78 years (mean ±
SEM, 62 ± 6 years) for nonsmokers and from 37 to 77 years (mean ±
SEM, 58 ± 5 years) for smokers. Postmortem intervals were 6 to 24 hours
(mean ± SEM, 16 ± 2 hours) for nonsmokers and 4 to 28 hours
(mean ± SEM, 18 ± 3 hours) for smokers. Ages and postmortem
intervals were not significantly different between smokers and nonsmokers.
There were 8 men and 1 woman among the nonsmokers, and 4 men and 3 women in
the group of smokers.
DISSECTION
Tissue blocks containing the LC were dissected as described previously19, 20 and stored in an ultracold freezer
(-83°C). Blocks were sectioned at 1-mm intervals (20-µm sections; -16°C)
in a transverse plane perpendicular to the floor of the fourth ventricle,
and sections were thaw-mounted onto gelatin-coated microscope slides. The
LC was sectioned sequentially throughout its entire length beginning near
its rostral end. The rostral border of the LC was defined by the frenulum,
and the caudal border was the caudal extent of the LC (at the level of the
motor nucleus of the trigeminal nerve), defined as the point at which neuromelanin-containing
cells in the LC region were no longer visible.
QUANTITATIVE AUTORADIOGRAPHY
The specific binding of [3H]Ro41-1049 to MAO-A,21 p-[125I]iodoclonidine ([125I]PIC)
to 2-adrenoceptors,22 and
[3H]nisoxetine to the norepinephrine transporter19
was measured by quantitative receptor autoradiography. Tyrosine hydroxylase
immunoreactivity was measured using a tissue transfer method.23
Binding of [3H]Ro41-1049 to MAO-A
Sections were incubated for 60 minutes at 37°C with 20nM [3H]Ro41-1049 (18.5 Ci [68.45 x 1010Bq]/mmol) in a Tris
buffer (pH, 7.4; Sigma Chemical Co, St Louis, Mo) containing 50mM Tris, 120mM
sodium chloride (NaCl), 5mM potassium chloride (KCl), 14mM magnesium chloride
(MgCl2), and 0.5mM ethyleneglycotetraacetic acid. Sections were
then washed 3 times (2 minutes each) in the ice-cold buffer. Nonspecific binding
was determined with 1µM clorgyline.
Binding of [125I]PIC to 2-Adrenoceptors
Sections were pre-incubated in a Tris-magnesium (Tris-Mg) buffer (170mM
Tris, 10mM MgCl2; pH, 7.6) at 23°C for 60 minutes. Sections
were then incubated for 90 minutes at 23°C with 300pM of [125I]PIC
(2200 Ci [8140 x 1010Bq]/mmol) in the Tris-Mg buffer. Sections
were then washed once for 10 minutes in the ice-cold buffer. Nonspecific binding
of [125I]PIC was determined with 10µM l-norepinephrine. The use of norepinephrine to define nonspecific binding
eliminated the influence of imidazoline sites in the calculation of specific
binding to 2-adrenoceptors.
Binding of [3H]Nisoxetine to the Norepinephrine Transporter
Sections were incubated at 4°C for 4 hours with 3.0nM [3H]nisoxetine
(82 Ci [303.4 x 1010Bq]/mmol) in a Tris
buffer (pH, 7.4) containing 50mM Tris, 300mM NaCl, and 5mM KCl. Sections were
then washed 3 times (5 minutes each) in the ice-cold buffer. Nonspecific binding
was determined with 1µM mazindol.
Sections and brain mash–calibrated [3H] standards were
apposed to [3H]-Hyperfilm (Amersham, Piscataway, NJ) and exposed
in x-ray cassettes at room temperature for 20 hours for [125I]PIC,
2 weeks for [3H]Ro41-1049, and 4 weeks for [3H]nisoxetine.
Film was processed with the GBX developer and fixer (Eastman Kodak, Rochester,
NY) at 17°C. After autoradiography, the same sections were lightly stained
with cresyl violet for aid in LC identification. Densitometric measurements
of autoradiograms were made using the Microcomputer Controlled Imaging Device
(MCID M2; Imaging Research Inc, St Catharines, Ontario). Locus coeruleus autoradiograms
were analyzed by simultaneously overlaying the image of the autoradiogram
with the image of the same histologically stained section. The smallest region
encompassing all neuromelanin-containing cell bodies was outlined. Specific
binding was defined as the difference between total and nonspecific binding.
The binding of radioligands to the left and right sides of the LC was measured
independently. Right- and left-side binding density was averaged because no
significant difference in binding between sides was observed.
TYROSINE HYDROXYLASE IMMUNOREACTIVITY
Adjacent sections (in duplicate) at the same LC levels from the same
subjects were transferred to an Immobilon-P membrane (Millipore Corp, Bedford,
Mass), immunoblotted for tyrosine hydroxylase, and quantified autoradiographically
using the MCID M2 as previously described.12
Nissl-stained sections were used to identify borders of the cellular region
of the LC. Optical densities of autoradiograms were standardized using an
optical density step-wedge (Imaging Research Inc).
STATISTICAL ANALYSIS
Repeated-measures analysis of variance (ANOVA) models were used to investigate
differences between smokers and nonsmokers. Measures of specific proteins
were obtained at 1-mm intervals of the LC to assure anatomical alignment along
its rostral-caudal axis for all subjects. The focus was the potential differences
in the rostral, middle, or caudal portions of the LC because of their different
projections, as noted in rat studies.24, 25, 26
Hence, measurements of the distance from the frenulum were averaged for the
rostral (0.5-2.5 mm), middle (3.5-6 mm), and caudal (7-9 mm) portions for
each subject. Mean values of these regions were compared for smokers and nonsmokers
at each of the 3 positions, with adjustments for multiple testing using the
Bonferroni adjustment. In addition to analyses of the 3 positions, we considered
quadratic modeling of measures from all 1-mm intervals to determine where
the maximum difference along the axis of the LC occurred between smokers and
nonsmokers. To facilitate statistical analysis, measures were transformed
to a natural logarithmic scale. Summary statistics are reported as the mean
± SEM for the transformed data. P<.05 was
considered significant.
RESULTS
Amounts of tyrosine hydroxylase immunoreactivity in the LC, measured
autoradiographically, were significantly lower in individuals with long-term
smoking histories compared with nonsmoking controls. A repeated-measures ANOVA
of 3 anatomically distinct levels of the LC revealed a significant difference
at the middle level, with a trend toward significance at the rostral and caudal
levels (Table 2; Figure 1A and Figure 2A).
Analysis of curves modeled to measurements of tyrosine hydroxylase at 1-mm
intervals (Figure 2A) did not demonstrate
a significant difference in quadrature between smokers and nonsmokers, but
did demonstrate a significant difference between amounts of tyrosine hydroxylase
(t13 = 2.75; P
= .02). Using a quadratic model to compute differences, the maximum difference
between smokers and nonsmokers appeared at a distance of 4 to 5 mm from the
frenulum, where the mean tyrosine hydroxylase amount for nonsmokers was 4.7
times higher than for smokers. Traditional Western blot analysis was performed
in homogenates of LC punches from some of the same subjects at the same LC
levels to confirm that tyrosine hydroxylase content was lower in samples from
smokers compared with those from nonsmokers (Figure 3).
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Table 2. Analyses of Tyrosine Hydroxylase at 3 Anatomical Levels Along
the Rostral-Caudal Axis of the Locus Coeruleus*
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Figure 1. Digitized autoradiograms of tyrosine
hydroxylase immunoreactivity (A) and of the specific binding of p-[125I]iodoclonidine to 2-adrenoceptors
(B) at multiple levels along the rostral-caudal axis of the locus coeruleus
(LC) from a nonsmoking subject (left panel, subject NS-2) and from an age-matched
subject who was a cigarette smoker (right panel, subject S-1). Panels are
oriented so that the top is rostral and the bottom is caudal along the LC
axis.
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Figure 2. The distribution of tyrosine hydroxylase
immunoreactivity (A), specific binding of p-[125I]iodoclonidine to 2-adrenoceptors (B), specific
binding of [3H]nisoxetine to the norepinephrine transporter (C),
and specific binding of [3H]Ro41-1049 to monoamine oxidase A (D)
along the rostral-caudal axis of the human locus coeruleus (LC) of smokers
(solid circles; n = 7) and nonsmokers (open circles; n = 8 or 9). Values are
the means of amounts of each group determined by the average of 4 estimations
(left and right sides of the LC, both in duplicate) made for each subject.
The abscissa is the distance from the frenulum along the rostral-caudal axis
of the LC. Density readings of tyrosine hydroxylase were transformed to natural
logarithms because of the departure of their distributions from normality
(P<.05).
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Figure 3. Western blotting of tyrosine hydroxylase
immunoreactivity in locus coeruleus (LC) tissues from a nonsmoker and a smoker
(same subjects as shown in Figure 1). For Western blotting, each well was
loaded with 50 µg of total protein from the middle level of the rostral-caudal
extent of the LC. The bottom panel (left and right) shows immunoreactive actin
probed with antiactin antibody on the same blots as a control for protein
loading and transfer.
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The specific binding of [125I]PIC to 2-adrenoceptors
was also significantly lower in the LCs of smokers compared with nonsmokers.
Repeated-measures ANOVA of the 3 anatomically distinct levels of the LC revealed
significant differences in amounts of [125I]PIC binding between
smokers and nonsmokers at rostral and middle levels, and a trend toward significance
at the caudal level (Table 3; Figure 1B and Figure 2B). Analysis of amounts of [125I]PIC binding
at 1-mm intervals (Figure 2B) demonstrated
a significant difference in quadrature (P<.001)
and in amounts (t14 = 2.93; P = .01) between smokers and nonsmokers. The maximum difference between
smokers and nonsmokers, computed using quadratic modeling, appeared at a distance
of 5 and 6 mm from the frenulum, where the mean amount of [125I]PIC
binding in nonsmokers was 1.8 times higher than that of smokers.
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Table 3. Analyses of 2-Adrenoceptor Binding at 3
Anatomical Levels Along the Rostral-Caudal Axis of the Locus Coeruleus*
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The binding of [3H]nisoxetine to the norepinephrine transporter
(Figure 2C) and of [3H]Ro41-1049
to MAO-A (Figure 2D) in the LC was
not significantly different between smokers and nonsmokers.
COMMENT
Our findings demonstrate a statistically significant association between
long-term smoking and low levels of tyrosine hydroxylase and 2-adrenoceptor binding in the human LC. One interpretation of these
data is that long-term smoking, either through direct or indirect effects
of components of tobacco smoke, down-regulates tyrosine hydroxylase and 2-adrenoceptors in the LC. The putative effects of smoking appear to
be relatively specific to these 2 proteins; smoking did not affect radioligand
binding to the norepinephrine transporter or MAO in the same subjects. Furthermore,
putative smoking-induced effects appear to be widespread in the LC and are
not limited to a single LC subregion. Because the LC is topographically organized
with respect to its projections,24, 25, 26
this latter finding implies widespread effects of cigarette smoking on noradrenergic
activity in the central nervous system.
A limitation of this study is that it is not possible to determine whether
cigarette smoking causes reductions in levels of tyrosine hydroxylase and 2-adrenoceptors or, alternatively, if this biochemical phenotype predisposes
an individual to the acquisition of a smoking habit. Further studies in humans
with smoking histories and in rats exposed to long-term smoke are required
to determine whether there is a cause or effect relationship. Another limitation
of the study is that there were more women in the smoking group than in the
nonsmoking group. To date, a relationship between sex and levels of tyrosine
hydroxylase or 2-adrenoceptors in the LC has not been observed,
although studies have not been specifically designed to address these potential
effects.
It is interesting to compare the putative effect of long-term smoking
on human LC biochemistry with effects produced by drugs known to modulate
LC biochemistry in rats. Repeated treatment of rats with antidepressant drugs
of multiple chemical classes down-regulates tyrosine hydroxylase in the LC,
an effect not observed following treatment with nonantidepressant compounds.10 Long-term treatment of rats with the smoking cessation
and antidepressant drug bupropion also down-regulates LC tyrosine hydroxylase.
Repeated treatment of rats with antidepressant drugs also reduces 2-adrenoceptor binding in the LC.11 In
contrast to the effects on tyrosine hydroxylase and 2-adrenoceptors,
repeated treatment of rats with the antidepressant desipramine or repeated
electroconvulsive shock has no effect on [3H]nisoxetine binding
to the norepinephrine transporter in the LC.27
The known effects of antidepressant drug treatment on rat LC biochemistry
are remarkably similar to the putative effects of smoking on human LC biochemistry.
Recently, elevated levels of tyrosine hydroxylase12
and higher amounts of 2-adrenoceptor binding13, 28
have been observed in the LCs of subjects with major depression and who commit
suicide compared with normal control subjects. The present association of
long-term smoking with reduced levels of LC tyrosine hyrdoxylase and 2-adrenoceptor binding is opposite to changes in the levels of these
proteins in major depression in humans. Together, preclinical and clinical
findings suggest that cigarette smoking produces antidepressant-like effects
on central noradrenergic neurons.
One of the known biological actions of tobacco that links smoking to
depression is the inhibition of MAO. MAO inhibitors, particularly MAO-A inhibitors,
are effective antidepressant drugs.29 The activities
of MAO-A and MAO-B are inhibited when rats are exposed to tobacco smoke but
not when they are exposed to nicotine alone.30
Similarly, an aqueous extract of cigarette smoke, or saliva obtained after
smoking, can irreversibly inhibit the action of MAO on a variety of the enzyme's
substrates in rat lung tissue.5 Significant
decreases in MAO-A and MAO-B in the brains of smokers relative to nonsmokers
or former smokers has recently been demonstrated using in vivo positron emission
tomography imaging with radiotracers specific for MAO-A and MAO-B.31, 32 In our study, radioligand binding
to MAO-A was reduced modestly but not significantly in the LCs of smokers
relative to nonsmokers. The lack of significant changes in MAO-A binding could
be a function of an insufficient sample size. Also, the time of death relative
to the last cigarette smoked was not known for the subjects included in this
study and would probably be highly variable, possibly contributing to variability
in MAO binding levels.
Long-term inhibition of MAO by components of cigarette smoke could produce
effects similar to those observed in our study, particularly given that long-term
treatment of rats with MAO inhibitors down-regulates LC tyrosine hydroxylase.10 Another biological component of tobacco that could
potentially induce changes in LC biochemistry is nicotine. Nicotine increases
the LC firing rate and stimulates the release of norepinephrine from LC neurons.33, 34 A single dose of nicotine increases
tyrosine hydroxylase messenger RNA in the LC.35
Nicotinic agonists have demonstrated antidepressant-like effects in an animal
model of depression.8, 9 Unfortunately,
the long-term effects of nicotine on LC activity and biochemistry have not
been studied.
This report is the first direct observation in the human brain (postmortem)
that long-term cigarette smoking is associated with neurochemical abnormalities
in the noradrenergic LC. These changes are opposite to those observed in the
LC in major depression12, 13 and
are similar to the effects observed in animals repeatedly treated with antidepressant
drugs. Such data argue that the high incidence of smoking in patients with
major depression and the difficulty with smoking cessation among this group
might be a partial result of smoking-induced neurochemical "corrections" of
biological abnormalities associated with this disorder. This evidence cannot
justify the use of tobacco in these individuals because of the adverse effects
of smoking. However, a thorough understanding of the neurochemical basis for
the high incidence of smoking in people with depression is needed to develop
better therapies for smoking cessation, particularly among those with major
depression.
AUTHOR INFORMATION
Accepted for publication May 2, 2001.
This work was supported by grants MH46692 (Dr Ordway) and MH45488 (Dr
Stockmeier) from the National Institutes of Health, Bethesda, Md, and a Young
Investigator Award from the National Alliance for Research on Schizophrenia
and Depression (Dr Klimek), Great Neck, NY.
We gratefully acknowledge John Haycock, PhD (Louisiana State University,
New Orleans, La), for supplying tyrosine hydroxylase antibody, and Grayson
Richards, PhD (Hoffmann-La Roche, Basel, Switzerland), for supplying radioligand
[3H]Ro41-1049. The excellent assistance of the medical examiner's
office in Cleveland, Ohio, is greatly appreciated.
From the Departments of Psychiatry and Human Behavior (Drs Klimek,
Zhu, Stockmeier, and Ordway), Pharmacology and Toxicology (Dr Ordway), and
Preventive Medicine (Dr May), University of Mississippi Medical Center, Jackson;
and the Departments of Psychiatry (Dr Meltzer and Mss Dilley and Konick) and
Psychology (Dr Overholser), Case Western Reserve University, Cleveland, Ohio.
Dr Meltzer is now located at the Division of Psychopharmacology, Department
of Psychiatry, Vanderbilt University Medical Center, Nashville, Tenn.
Corresponding author: Gregory A. Ordway, PhD, Department of Psychiatry
and Human Behavior, University of Mississippi Medical Center, 2500 N State
St, Jackson, MS 39216-4505 (e-mail: gordway{at}psychiatry.umsmed.edu).
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