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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.
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.
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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