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

Abstract

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.

Site-specific overexpression of corticotropin-releasing hormone (CRH) in the mouse brain – modelling central CRH system hyperactivity

“…This result is in accordance to the data from the other two CRH-Tg mouse lines (van Gaalen et al, 2002) (Dirks et al, 2001) and this finding was also in agreement with studies showing that icv CRH administration reduces immobility time in forced swimming in rats and it has been proposed that this may also be the result of increased anxiety (Butler et al, 1990).…”

A Centrally Acting, Anxiolytic Angiotensin II AT1 Receptor Antagonist Prevents the Isolation Stress-Induced Decrease in Cortical CRF1 Receptor and Benzodiazepine Binding

“…There is a reciprocal relationship between the brain CRF and sympathetic systems, and CRH contributes to activation of the locus coeruleus during stress (Berridge and Waterhouse, 2003). Stress increases CRF concentrations in the locus coeruleus (Chappell et al, 1986), local application of CRF in the locus coeruleus induces behavioral activation (Butler et al, 1990), and i.c.v. administration of a CRF antagonist blunts the stress-induced increase in extracellular norepinephrine levels in the prefrontal cortex (Shimizu et al, 1994).…”

Elevated Concentrations of CRF in the Locus Coeruleus of Depressed Subjects

“…However, the effects of CRF on LC firing rates can be desensitized by 1 or 5 days of prior (30 min) footshock stress (Curtis et al, 1995) or intracerebral application of CRF (Conti and Foote, 1996), indicating different responses of LC firing rates to CRF depending upon the quantity and quality of stressor exposure. The ability of CRF to induce behavioral correlates of fear and anxiety (defensive withdrawal) after intraventricular delivery is potentiated by infusion into the LC region (Butler et al, 1990) and two weeks of chronic, unpredictable stress produces increased concentrations of CRF in the LC of laboratory rats (Chappell et al, 1986). A CRF receptor antagonist applied to the LC attenuates the defensive withdrawal induced by prior immobilization (Smagin et al, 1996).…”

“…Infusion of synthetic CRF into specific brain regions of several animal species elicits behaviors similar to fear and anxiety (Koob and Britton, 1990;Butler et al, 1990) and alteration of endogenous CRF concentrations has been demonstrated in several brain regions after chronic or acute exposure of laboratory animals to stressful stimuli that result in behavioral responses associated with fear and anxiety (Chappell et al, 1986;Bissette, 2001). Among these brain regions is the locus coeruleus (LC).…”