Participation of brainstem monoaminergic nuclei in behavioral depression

Several lines of research have now suggested the controversial hypothesis that the central noradrenergic system acts to exacerbate depression as opposed to having an antidepressant function. If correct, lesions of this system should increase resistance to depression, which has been partially but weakly supported by previous studies. The present study reexamined this question using two more recent methods to lesion noradrenergic neurons in mice: intraventricular (ivt) administration of either the noradrenergic neurotoxin, DSP4, or of a dopamine-β-hydroxylase-saporin immunotoxin (DBH-SAP ITX) prepared for mice. Both agents given 2 weeks prior were found to significantly increase resistance to depressive behavior in several tests including acute and repeated forced swims, tail suspension and endotoxin-induced anhedonia. Both agents also increased locomotor activity in the open field. Cell counts of brainstem monoaminergic neurons, however, showed that both methods produced only partial lesions of the locus coeruleus and also affected the dorsal raphe or ventral tegmental area. Both the cell damage and the antidepressant and hyperactive effects of ivt DSP4 were prevented by a prior i.p. injection of the NE uptake blocker, reboxetine. The results are seen to be consistent with recent pharmacological experiments showing that noradrenergic and serotonergic systems function to inhibit active behavior. Comparison with previous studies utilizing more complete and selective LC lesions suggest that mouse strain, lesion size or involvement of multiple neuronal systems are critical variables in the behavioral and affective effects of monoaminergic lesions and that antidepressant effects and hyperactivity may be more likely to occur if lesions are partial and/or involve multiple monoaminergic systems.