REDUCED LEVELS OF NOREPINEPHRINE TRANSPORTERS IN THE LOCUS-COERULEUS IN MAJOR DEPRESSION

The norepinephrine transporter (NET) is a membrane protein responsible for termination of the action of synaptic norepinephrine and is a sit e of action of many drugs used to treat major depression. The present study determined whether the binding of [H-3]nisoxetine to the NET is altered in the locus coeruleus (LC) in major depression, using brain t issue collected postmortem from subjects diagnosed with major depressi on and from age-matched normal control subjects. Thirteen of the 15 ma jor depressive subjects studied died by suicide. The distribution of [ H-3]nisoxetine binding along the rostro-caudal axis of the nucleus was uneven and was paralleled by a similar uneven distribution of neurome lanin-containing cells in both major depressives and psychiatrically n ormal control subjects. The binding of [H-3]nisoxetine to NETs in the midcaudal portion of the LC from major depressive subjects was signifi cantly lower than that from age-matched, normal control subjects. The binding of [H-3]nisoxetine to NETs in other regions of the LC was simi lar in major depressives and control subjects. In contrast to reductio ns in binding to NETs, there were no significant differences in the nu mber of noradrenergic cells at any particular level of the LC between major depressives and normal control subjects. The decreased binding o f [H-3]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.