Corticotropin-Releasing Factor: Evidence for a Neurotransmitter Role in the Locus ceruleus during Hemodynamic Stress

Abstract

Corticotropin-releasing factor (CRF) is localized in fibers in the noradrenergic nucleus locus ceruleus (LC) and alters LC discharge characteristics when administered centrally. To determine whether CRF functions as a neurotransmitter in the LC during stress, the effects of hemodynamic stress on LC discharge were compared to those of CRF. Hemodynamic stress elicited by intravenous nitroprusside infusion produced identical effects on LC spontaneous and sensory-evoked discharge as those reported for centrally administered CRF. Thus, nitroprusside increased LC spontaneous discharge rates, and disrupted LC discharge evoked by sensory stimuli such that the stimuli were less effective in producing phasic increases in LC discharge. The neuronal effects of nitroprusside were completely blocked by central administration of the CRF receptor antagonist, α helical CRF9–41, but not by pretreatment with dexamethasone which blocks stress-elicited hypophyseal CRF release. The present results confirm other reports of LC activation by stressors, and extend these studies by demonstrating that, in certain circumstances, this activation is dependent on endogenous CRF. This study supports the concept that CRF functions as a neurotransmitter in the LC in the initiation of stress responses.

Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men

“…Both electrophysiological and biochemical studies have shown that CRH increases the spontaneous discharge rate of LC neurons, increases norepinephrine release and increases tyrosine hydroxylase protein levels in the LC. 21,23,[50][51][52] Furthermore, depending on the type of stressor, the stress-induced activation of LC neurons appears to be mediated by CRH presumably released from terminals within the LC region. 21,22,53 These findings are consistent with the elevation in CRH levels in the LC following stress.…”

“…21,23,[50][51][52] Furthermore, depending on the type of stressor, the stress-induced activation of LC neurons appears to be mediated by CRH presumably released from terminals within the LC region. 21,22,53 These findings are consistent with the elevation in CRH levels in the LC following stress. 54 Recent studies have also provided evidence of a neurotransmitter role for CRH on serotonin neurons in the DR. For example, injection of CRH into the ventricles or directly into the DR of rats inhibited the discharge rate of serotonin neurons in the DR. 24,25 However, Lowry et al, 26 using an in vitro slice preparation, reported that CRH had no effect on the firing rate of serotonin neurons from control rats, but significantly increased the firing rate of serotonin neurons from rats previously exposed to repeated restraint stress.…”

“…In particular, both electrophysiological and biochemical studies have shown that CRH is involved in mediating the effects of stress on norepinephrine neurotransmission specifically at the level of the noradrenergic neurons in the locus coeruleus (LC). [21][22][23] Furthermore, recent electrophysiological studies have found that CRH has both excitatory and inhibitory effects on serotonin neurons in the dorsal raphe nucleus. [24][25][26] Given the evidence from animal studies supporting a functional role of CRH on LC and raphe neurons, it is interesting that both clinical and postmortem brain studies have documented alterations in various noradrenergic [27][28][29] and serotonergic [30][31][32] parameters in depressed subjects.…”

Cerebral Neurochemical Mechanisms in Stress and Anxiety

“…Nitroprusside is known to increase the rate of discharge of LC noradrenergic neurons, presumably because of the consequent acute hypotension (32). A relationship between CRF and noradrenergic neurons may be functional during hypotension because &rfth d.p.…”

Pituitary Gland: Neuropeptides, Neurotransmitters and Growth Factors

“…These neurons project to the ME where they secrete CRH into the hypophyseal portal blood (19). These PVN neurons also project to various brainstem nuclei, such as the locus coeruleus, the parabrachial and vagal nuclei where CRH may be involved in modulating hemodynamic function and in coordination of stress responses (85). CRH neurons also are present in the amygdala and in the cerebral cortex, however, the function of CRH in these regions is currently unknown (78,79).…”