Selective Activation of Corticotropin-Releasing Factor-2 Receptors on Neurochemically Identified Neurons in the Rat Dorsal Raphe Nucleus Reveals Dual Actions

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Abstract
The dorsal raphe (DR)-serotonin (5-HT) system has been implicated in stress-related psychiatric disorders. Stress may impact on this system through corticotropin-releasing factor (CRF), which densely innervates the DR. CRF binds to CRF-R1 and CRF-R2 receptors in the DR and has complex and opposing effects depending on the dose used and the endpoint examined. To clarify the impact of CRF on the DR-5-HT system, the effects of selectively activating CRF-R2 receptors (the predominant subtype) on extracellular DR neuronal activity were examined in halothane-anesthetized rats. Because the DR is neurochemically heterogeneous, when possible, neurons were labeled with neurobiotin for subsequent neurochemical classification as 5-HT or non-5-HT. Relatively low doses of urocortin II (UII) (0.1-10 ng) injected into the DR inhibited most (79%;n= 34) neurons, whereas a higher dose (30 ng) inhibited 28% and activated 41% (n= 29). An analysis of effects on neurochemically identified neurons revealed that 5-HT neurons were inhibited by 0.1-10 ng of UII and activated by 30 ng of UII. Activation of 5-HT neurons by 30 ng of UII likely resulted from disinhibition because the majority of non-5-HT neurons were inhibited by this dose. Antisauvagine-30, but not antalarmin, antagonized UII, implicating CRF-R2 receptors in the effects. The results suggest that activation of CRF-R2 on DR-5-HT neurons inhibits neuronal activity, whereas activation of CRF-R2 receptors on non-5-HT neurons may indirectly excite DR-5-HT neurons through disinhibition. Importantly, the tone of the DR-5-HT system can be regulated in a dynamic manner through CRF-R2 activation, being either decreased or increased depending on the level of endogenous or exogenous ligand.