Ultrastructural evidence for a role of γ-aminobutyric acid in mediating the effects of corticotropin-releasing factor on the rat dorsal raphe serotonin system

The dorsal raphe nucleus (DRN) serotonin (5-HT) system has been implicated in acute responses to stress and in stress-related psychiatric disorders such as anxiety and depression. Substantial findings suggest that the neuropeptide corticotropin-releasing factor (CRF) is instrumental in modulating the activity of this system during stress. Because the DRN is neurochemically heterogeneous, dual immunoelectron microscopy was used to examine cellular substrates for interactions between CRF and either 5-HT or gamma-aminobutyric acid (GABA) in the dorsolateral and ventromedial DRN. CRF immunoreactivity was identified primarily within axon terminals, where immunolabeling was particularly enriched in dense-core vesicles. Although CRF terminals targeted 5-HT-containing dendrites in the dorsolateral DRN (16%; n = 251 terminals), synaptic contacts with dendrites that lacked detectable 5-HT immunolabeling were more numerous (48%). In contrast, dual labeling for CRF and GABA (n = 240 terminals) in the dorsolateral DRN revealed that substantially more CRF terminals contacted GABA dendrites (42%) as opposed to unlabeled dendrites (29%). In the ventromedial DRN, contacts between CRF axon terminals and either 5-HT-labeled dendrites or GABA-containing dendrites were fewer than in the dorsolateral DRN. As in the dorsolateral DRN, CRF terminals more frequently contacted GABA dendrites than 5-HT dendrites (30% vs. 8%, respectively). The findings support physiological studies suggesting that CRF has both direct and indirect effects on DRN-5-HT neurons and further implicate GABA as a primary mediator by which CRF and stressors alter the activity of the DRN-5-HT system. (C) 2004 Wiley-Liss, Inc.