A neurochemically distinct dorsal raphe-limbic circuit with a potential role in affective disorders

Abstract

The serotonergic system arising from the dorsalraphe nucleus (DR) has long been implicated in psychiatric disorders, and is considered one site of action of classicalanxiolytic and antidepressant agents. Recent studies implicate the DR as a site of action of novelanxiolyticand antidepressant agents that target neuropeptide systems, such as corticotropin-releasing factor (CRF) and neurokinin 1 (NK1)antagonists. The present study identified unique characteristics of the dorsomedialDR that implicate this particular subregion as a keycomponent of a circuit, which may be targeted by these diverse psychotherapeutic agents. First, it was observed that a cluster of CRF-containing cellbodies was present in the dorsomedialDR of colchicine-treated rats. Dual-labeling immunohistochemistry revealed thatalmost allCRF-containing neurons were serotonergic, implicating CRF as a cotransmitter with serotonin in this subpopulation of DRneurons. Moreover, dendrites laden with immunoreactivity for NK1 had a striking topographic distribution surrounding and extendinginto the dorsomedialsubregion of the DR, suggesting that NK1 receptor ligands may selectively impact the dorsomedialDR. Finally, anterograde tract tracing from the dorsomedialDR combined with CRF immunohistochemistry revealed that CRF-containing axons fromthis subregion project to CRF-containing neurons of the centralnucleus of the amygdala. Taken together, the present results revealacircuit whereby NK1 receptor activation in the dorsomedialDR can impact on limbic sources of CRF that have been implicated inemotionalresponses. This circuit may be relevant for understanding the mechanism of action of novelpsychotherapeutic agents that actthrough NK1 or CRF receptors. © 2003 Nature Publishing Group.