Corticotropic-releasing hormone and serotonin interact in the human brainstem: Behavioral implications

The objective of this human post mortem study was to determine whether neur ons which synthesize corticotropic-releasing hormone and serotonin form cir cuits implicated in the pathophysiology of major depression and suicide. Fo r the first time, a sensitive, dual immunocytochemical procedure was used t o identify circuits formed by corticotropic-releasing hormone-synthesizing and serotonergic cell groups. Corticotropic-releasing hormone-immunoreactiv e varicose fibers and puncta with morphological characteristics of terminal s were labeled in the midline raphe, periventricular gray and pontine parab rachial complex, on single-labeled tissues processed immunocytochemically w ith a rabbit antibody to rat/human corticotropic-releasing hormone. Presump tive synaptic interactions with monoaminergic neurons were demonstrated wit h dual labeling techniques. Corticotropic-releasing hormone-immunoreactive terminals apposed neuronal somata and primary dendrites of serotonergic neu rons in the pontine raphe. Serotonergic neurons were immunolabeled with a m ouse antibody to phenylalanine hydroxylase, an enzyme with substantial sequ ence homology to tryptophan hydroxylase. Interactions in the lateral para b rachial nucleus were suggested by precise overlap of corticotropic-releasin g hormone and serotonergic terminal fields. Corticotropic-releasing hormone projections were confirmed to noradrenergic neurons containing neuromelani n in the locus ceruleus. Maps of corticotropic-releasing hormone fiber traj ectories suggest that these pathways may derive from the forebrain and, loc ally, from the human homologue of Barrington's nucleus-a neurochemically sp ecialized division of the laterodorsal tegmental complex. Chemosensory func tions were predicted by novel evidence for corticotropic-releasing hormone- and monoaminergic neurovascular and subependymal fiber plexuses. In conclusion, corticotropic-releasing hormone may influence the activity o f two major monoaminergic cell systems implicated in the stress-diathesis m odel of mental illness, through neural and humoral mechanisms. (C) 1999 IBR O. Published by Elsevier Science Ltd.