The Locus Coeruleus as a Site for Integrating Corticotropin‐Releasing Factor and Noradrenergic Mediation of Stress Responsesa

Abstract

Anatomic and electrophysiologic studies have provided evidence that CRF meets some of the criteria as a neurotransmitter in the noradrenergic nucleus, the locus coeruleus (LC), although some of the criteria have yet to be satisfied. Thus, immunohistochemical findings suggest that CRF innervates the LC, but this must be confirmed at the ultrastructural level. CRF alters discharge activity of LC neurons and these effects are mimicked by some stressors. Moreover, the effects of hemodynamic stress on LC activity are prevented by a CRF antagonist. However, it has not been demonstrated that stimulation of CRF neurons that project to the LC activates the LC or that the effects of such stimulation are prevented by a CRF antagonist. The role of CRF in LC activation by stressors other than hemodynamic stress needs to be determined. It could be predicted that the effects of CRF neurotransmission in the LC during stress would enhance information processing concerning the stressor or stimuli related to the stressor by LC target neurons. One consequence of this appears to be increased arousal. Although this may be adaptive in the response to an acute challenge, it could be predicted that chronic CRF release in the LC would result in persistently elevated LC discharge and norepinephrine release in targets. This could be associated with hyperarousal and loss of selective attention as occurs in certain psychiatric diseases. Manipulation of endogenous CRF systems may be a novel way in which to treat psychiatric diseases characterized by these maladaptive effects.

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

“…Particularly intriguing are recent studies demonstrating a role for norepinephrine in the bed nucleus of the stria terminalis in the conditioned place aversions associated with opiate withdrawal (Delfs et al, 2000). Because norepinephrine may release CRF in the basal forebrain, and CRF activates norepinephrine function in the pons, there is the possibility of a feedforward system involved in the aversive stimulus effects of opiate withdrawal as well as stress in general (Koob, 1999;Valentino et al, 1993).…”

“…The present results with the CRF 1 antagonist antalarmin support this hypothesis. Given the known neuroanatomical, synaptic, and functional interaction of norepinephrine and CRF (Koob, 1999;Valentino et al, 1993), it is possible that these systems might be important therapeutic targets that mediate the aversive stimulus effects of opiate dependence.…”

Drug Addiction, Dysregulation of Reward, and Allostasis

“…A number of brain sites currently hypothesized to be particularly important for the behavioral effects of CRF, specifically with regard to the role of CRF in arousal and behavioral responses to stress, are closely linked to the brain norepinephrine systems including the locus coeruleus, the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala (Valentino et al 1993;Van Bockstaele et al 1998). Thus, stress, either autonomic or emotional, activates CRF release in the nucleus locus coeruleus which in turn stimulates activity in the locus coeruleus.…”

“…Central nervous system norepinephrine systems have been considered as having a role in arousal/alerting functions (Robbins and Everitt 1995). Stress increases the turnover of norepinephrine in many terminal projection areas of the locus coeruleus (Korf et al 1973) and increases extracellular norepinephrine in the hippocampus (Abercrombie et al 1988), and a variety of stressors increase the discharge rate of locus coeruleus neurons (Valentino et al 1993).…”

“…Central nervous system norepinephrine systems have been considered as having a role in arousal/alerting functions (Robbins and Everitt 1995). Stress increases the turnover of norepinephrine in many terminal projection areas of the locus coeruleus (Korf et al 1973) and increases extracellular norepinephrine in the hippocampus (Abercrombie et al 1988), and a variety of stressors increase the discharge rate of locus coeruleus neurons (Valentino et al 1993).A number of brain sites currently hypothesized to be particularly important for the behavioral effects of CRF, specifically with regard to the role of CRF in arousal and behavioral responses to stress, are closely linked to the brain norepinephrine systems including the locus coeruleus, the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala (Valentino et al 1993;Van Bockstaele et al 1998). Thus, stress, either autonomic or emotional, activates CRF release in the nucleus locus coeruleus which in turn stimulates activity in the locus coeruleus.…”