Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus

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The present series of experiments tested the hypothesis that the behavioral activating and anxiogenic effects produced by intraventricular administration of corticotropin-releasing factor (CRF) may be mediated by noradrenergic neurons in the brain-stem locus coeruleus (LC). Results showed that infusion of CRF into the LC (100 ng) significantly increased nonambulatory spontaneous motor activity measured in photocell cages; ambulatory (i.e., locomotor) activity was not altered. In the modified Porsolt swim test, which examines arousal and agitation in a stressful situation, significant behavioral activation (i.e., decreased floating) was seen following infusion of CRF (10 ng) into the LC; a 500 ng dose of CRF was necessary to produce similar effects following infusion into the lateral ventricle. The results of these 2 tests suggest that the behavioral activating effects of CRF in the LC may be related to arousing or stress-related effects, rather than to increased locomotor activity per se. Anxiogenic activity was assessed in animals placed in an open field containing a small, darkened compartment. Infusion or CRF into the LC (1-100 ng) significantly increased the time spent in the compartment and decreased the amount of time spent exploring the outside of the compartment or venturing into the inner squares of the open field, all indices of anxiogenic behavior. Biochemical studies showed that bilateral infusion of CRF into the LC produced significant increases in the concentration of the norepinephrine metabolite 3,4-dihydroxyphenylglycol in such forebrain projection areas of the LC as the amygdala and posterior hypothalamus. These data, taken together, suggest that CRF produces its behavioral activating and anxiogenic effects, at least in part, by increasing the activity of LC noradrenergic neurons.