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Volume 17, Number 21,
Issue of November 1, 1997
pp. 8451-8458
Copyright ©1997 Society for Neuroscience
Reduced Levels of Norepinephrine Transporters in the Locus
Coeruleus in Major Depression
Received June 20, 1997; revised Aug. 19, 1997; accepted Aug. 22, 1997.
Violetta Klimek1,
Craig Stockmeier2,
James Overholser2,
Herbert Y. Meltzer2,
Sheila Kalka1,
Ginny Dilley2, and
Gregory A. Ordway1
1 Departments of Psychiatry and Human Behavior and
Pharmacology and Toxicology, University of Mississippi Medical Center,
Jackson, Mississippi 39216-4505, and 2 Department of
Psychiatry, Case Western Reserve University, Cleveland, Ohio
44106-5000
The norepinephrine transporter (NET) is a membrane protein
responsible for termination of the action of synaptic norepinephrine and is a site of action of many drugs used to treat major depression. The present study determined whether the binding of
[3H]nisoxetine to the NET is altered in the locus
coeruleus (LC) in major depression, using brain tissue collected
postmortem from subjects diagnosed with major depression and from
age-matched normal control subjects. Thirteen of the 15 major
depressive subjects studied died by suicide. The distribution of
[3H]nisoxetine binding along the rostro-caudal
axis of the nucleus was uneven and was paralleled by a similar uneven
distribution of neuromelanin-containing cells in both major depressives
and psychiatrically normal control subjects. The binding of
[3H]nisoxetine to NETs in the midcaudal portion of
the LC from major depressive subjects was significantly lower than that
from age-matched, normal control subjects. The binding of
[3H]nisoxetine to NETs in other regions of the LC
was similar in major depressives and control subjects. In contrast to
reductions in binding to NETs, there were no significant differences in
the number of noradrenergic cells at any particular level of the LC between major depressives and normal control subjects. The decreased binding of [3H]nisoxetine to NETs in the LC in
major depression may reflect a compensatory downregulation of this
transporter protein in response to an insufficient availability of its
substrate (norepinephrine) at the synapse.
Key words:
locus coeruleus;
major depression;
suicide;
norepinephrine transporters;
tricyclic antidepressants;
norepinephrine;
noradrenergic;
norepinephrine uptake
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