Reduced levels of norepinephrine transporters in the locus coeruleus in major depression

Abstract

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.

Fig. 1.

The distribution of specific binding of [³H]nisoxetine to NETs along the rostro-caudal axis of the LC from nine subjects diagnosed with major depression (▪) and nine age-matched psychiatrically normal control subjects (○). Theabscissa is the distance from the frenulum in the caudal direction. Values are the average of four estimations (left and right sides in duplicate) for every subject. Asterisksindicate statistically significant differences between groups (*p < 0.05; **p < 0.01).

Fig. 2.

A, Digitized autoradiograms of the specific binding of [³H]nisoxetine to NETs in the LC from a psychiatrically normal control subject and an age-matched subject diagnosed with major depression. Images of [³H]nisoxetine binding to NETs are shown at a transverse level through the LC ∼8 mm caudal to the frenulum. Autoradiographic images were generated by digitally subtracting the image of nonspecific binding of [³H]nisoxetine from the image of the total binding with the aid of a computer.B, Digitized images of tissue sections used to generate the autoradiograms shown in A (sections were stained with cresyl violet). Dark spots are neuromelanin-containing cells of the LC. For densitometric analyses, the smallest region encompassing all LC cell bodies containing neuromelanin pigment was outlined in the histological image, and this outline was projected onto the precisely overlaid image of the autoradiogram.

Fig. 3.

Numbers of neuromelanin-containing cells along rostro-caudal extent of the LC from nine subjects diagnosed with major depression (▪) and nine age-matched psychiatrically normal control subjects (○; same subject pairs as shown in Fig. 1). Theabscissa is the distance from the frenulum in the caudal direction. Values are the average of four estimations (left and right sides in duplicate) for every subject.

Fig. 4.

Relationship between neuromelanin-containing cell counts and the binding of [³H]nisoxetine to NETs at all levels of the LC from nine psychiatrically normal control subjects (A; r² = 0.47; p < 0.001) and from nine subjects diagnosed with major depression (B;r² = 0.27; p < 0.001).

Fig. 5.

Specific binding of [³H]nisoxetine to NETs at a transverse level of LC cut ∼2.5 mm caudal to the frenulum (Rostral LC) and 8 mm caudal to frenulum (Caudal LC) in 15 age-matched pairs of major depressive (MD) and control subjects (Control). *Significant difference from the control group at p < 0.01.

Fig. 6.

Specific binding of [³H]nisoxetine to NETs in the caudal portion of dorsal raphe and in the median raphe estimated in sections from nine psychiatrically normal control subjects (open bars) and nine subjects diagnosed with major depression (filled bars). Binding was analyzed in sections cut at the rostral portion of LC, ∼0.4 mm (1), 1.4 mm (2), and 2.5 mm (3) caudal to the frenulum. There were no statistically significant differences.