Discrete local application of corticotropin-releasing factor increases locus coeruleus discharge and extracellular norepinephrine in rat hippocampus

Abstract

The most prominent afferents impinging upon the noradrenergic neurons of the locus coeruleus (LC) utilize GABA and glutamate. However, peptide neurotransmitters such as galanin, neuropeptide Y, and corticotropin-releasing factor (CRF) have also been localized to LC afferents. The evidence for CRF modulation of LC activity was examined in the present studies. Specifically, the impact of local CRF administration on both LC-NE discharge characteristics and release of norepinephrine (NE) in hippocampus was determined. First, the ability of CRF microinfused into the LC area to increase NE efflux in the dorsal hippocampus was determined using in vivo microdialysis techniques in awake rats. CRF into the LC dose-dependently increased extracellular NE in the ipsilateral hippocampus. Second, a more detailed analysis was performed in halothane-anesthetized rats by characterizing the electrophysiological activity of LC-NE neurons in response to local application of CRF. Changes in the firing rate and pattern of single LC-NE neurons were measured while simultaneously monitoring the extracellular level of NE in hippocampus. A dose of 30 ng CRF applied directly into LC via pressure ejection elicited an 88% increase in the discharge rate of LC-NE neurons and increased the incidence of burst firing from 14% to 33%. This manipulation simultaneously increased extracellular NE in hippocampus by 63%. The CRF-induced increases in discharge rate of LC-NE neurons and extracellular NE efflux in hippocampus were prevented by prior i.c.v. administration of the CRF antagonist, d-PheCRF(12-41 )(3 microg / 3 microl). The present findings demonstrate that CRF applied directly into the LC increases both the activity of LC-NE neurons and the release of NE in an LC terminal region. The shift in activity of LC-NE neurons to more burst-like firing in response to CRF may provide a means for enhanced release of NE in LC projection fields. This is the first report to demonstrate a dose-dependent increase in extracellular NE levels evoked by intra-LC infusion of CRF in unanesthetized animals.