Depression and anxiety: Role of the locus coeruleus and corticotropin-releasing factor

Weiss, Jay M.; Stout, Julie C.; Aaron, Mark F.; Quan, Ning; Owens, Michael J.; Butler, Pamela D.; Nemeroff, Charles B.

doi:10.1016/0361-9230(94)90170-8

Cited by 144 publications

(84 citation statements)

References 55 publications

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“…These findings are consistent with a broader literature that have implicated CRF, and activation of noradrenergic neurons at the LC in particular, in the mediation of responses to stress and anxiety (Carrasco and Van de Kar 2003;Koob 1999;Matsuzaki et al 1989;Melia and Duman 1991;Reyes et al 2006;Weiss et al 1994). The LC is a major target of CRF neurotransmission in the brain (Van Bockstaele et al 1996) and is positioned to influence the functioning of the entire nervous system though modulation of noradrenergic activity (Abercrombie and Jacobs In agreement with its attenuation of burying responses to CRF administration, DSP-4 pretreatment also decreased the duration of probe burying in the conditioned defensive burying test, which is considered a validated rat test of anxiety (Treit et al 1981).…”

Section: Burying Behavior Is Mediated By Forebrain Nesupporting

confidence: 91%

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

et al. 2008

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Rationale-Central administration of corticotropin-releasing factor (CRF) elicits a specific pattern of behavioral responses resembling a stress-like state, and is anxiogenic in rodent models of anxiety.Objectives-Specific behaviors evoked by the administration of CRF were measured. The roles of CRF receptor subtypes and that of serotonergic and noradrenergic systems in mediating these responses were studied.Methods-Burying, grooming and head shakes were quantified in rats following intracerebroventricular administration of CRF and urocortin II and after pretreatment with antagonists. The role of forebrain norepinephrine in the behavioral responses to CRF (0.3 μg) was examined following pretreatment with the neurotoxin DSP-4 and that of serotonin after depletion using systemic administration of para-chlorophenylalanine (p-CPA).Results-CRF at 0.3 and 3.0 μg caused robust increases in burying, grooming and head shakes, but urocortin II was ineffective. Pretreatment with either antalarmin or propranolol significantly attenuated the CRF-evoked behaviors. Destruction of forebrain NE pathways blocked spontaneous burying behavior elicited by CRF and conditioned burying directed towards an electrified shock probe. In contrast, depletion of 5-HT selectively attenuated CRF-evoked grooming.Conclusions-Overt behavioral responses produced by CRF, burying, grooming, and head shakes, appeared to be mediated through the CRF 1 receptor. Spontaneous burying behavior evoked by CRF or conditioned burying directed towards a shock probe were disrupted by lesion of the dorsal noradrenergic bundle and may represent anxiety-like behavior caused by CRF activation of the LC. In contrast, CRF-evoked increases in grooming were dependent on serotonin.

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Section: Burying Behavior Is Mediated By Forebrain Nesupporting

confidence: 91%

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

et al. 2008

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“…Further evidence for modulation of CRH expression in structures comprising this sensory integration pathway (e.g. in parabrachial nucleus) has been emerging (50,51). Clearly, this proposed, chemically specified (CRH-CRF 2 ) pathway functions within the broader context of neuroanatomical circuits using several neurotransmitters to influence HPA function.…”

Section: How Do Sensory Signals Resulting From Early-life Handling Almentioning

confidence: 99%

Down-Regulation of Hypothalamic Corticotropin-Releasing Hormone Messenger Ribonucleic Acid (mRNA) Precedes Early-Life Experience-Induced Changes in Hippocampal Glucocorticoid Receptor mRNA**This work was supported by NIH Grants NS-28912 and NS-39307.

et al. 2001

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Early-life experiences, including maternal interaction, profoundly influence hormonal stress responses during adulthood. In rats, daily handling during a critical neonatal period leads to a significant and permanent modulation of key molecules that govern hormonal secretion in response to stress. Thus, hippocampal glucocorticoid receptor (GR) expression is increased, whereas hypothalamic CRH-messenger RNA (mRNA) levels and stress-induced glucocorticoid release are reduced in adult rats handled early in life. Recent studies have highlighted the role of augmented maternal sensory input to handled rats as a key determinant of these changes. However, the molecular mechanisms, and particularly the critical, early events leading from enhanced sensory experience to long-lasting modulation of GR and CRH gene expression, remain largely unresolved.To elucidate the critical primary genes governing this molecular cascade, we determined the sequence of changes in GR-mRNA levels and in hypothalamic and amygdala CRH-mRNA expression at three developmental ages, and the temporal relationship between each of these changes and the emergence of reduced hormonal stress-responses. Down-regulation of hypothalamic CRH-mRNA levels in daily-handled rats was evident already by postnatal day 9, and was sustained through postnatal days 23 and 45, i.e. beyond puberty. In contrast, handling-related up-regulation of hippocampal GR-mRNA expression emerged subsequent to the 23rd postnatal day, i.e. much later than changes in hypothalamic CRH expression. The hormonal stress response of handled rats was reduced starting before postnatal day 23. These findings indicate that early, rapid, and persistent changes of hypothalamic CRH gene expression may play a critical role in the mechanism(s) by which early-life experience influences the hormonal stress-response long-term.EARLY-LIFE EXPERIENCE influences both hormonal and behavioral responses to stress throughout life (1-5). In the human, early-life experiences may modulate stress-responses and coping, with long-term implications for emotional health and cognitive function (5). In rats, daily handling during a critical neonatal period leads to a significantly reduced stress response (compared with animals raised without any disturbance) that persists throughout

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“…In the parabrachial nucleus, an area which receives CRF projections from the central nucleus of the amygdala, an increase in CRF immunoreactvity was also observed. We have previously shown that local infusion of CRF into the parabrachial nucleus increased both depression-and anxiety-like behaviors suggesting that at least some of the signs of depression and anxiety observed in adult animals subjected to maternal separation during infancy may be mediated through increased CRF activity in the parabrachial nucleus (Weiss et al 1994). In fact, rats exposed to maternal separation show increased expression of CRF mRNA in the central nucleus of amygdala, a brain region involved in the autonomic, endocrine and behavior responses to stress (Menzaghi et al 1993), and increased CRF peptide content in terminal fields in the area of the LC (Plotsky et al 1998).…”

Section: Preclinical Studies Of Early-life Stressmentioning

confidence: 99%

“…Moreover, microinjections of CRF into the LC decrease open-field activity and increase defensive withdrawal, i.e. time spent in a darkened corner of the open-field and an increase in nonambulatory movement (Butler et al 1990, Weiss et al 1994. These behaviors indicate an increase in anxiety after CRF administration into the LC.…”

Section: Crf and Anxietymentioning

confidence: 99%

The role of corticotropin-releasing factor in depression and anxiety disorders

Arborelius¹,

Mj²,

Plotsky³

et al. 1999

Journal of Endocrinology

1,238

688

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Corticotropin-releasing factor (CRF), a 41 amino acidcontaining peptide, appears to mediate not only the endocrine but also the autonomic and behavioral responses to stress. Stress, in particular early-life stress such as childhood abuse and neglect, has been associated with a higher prevalence rate of affective and anxiety disorders in adulthood. In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitaryadrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics.

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Depression and anxiety: Role of the locus coeruleus and corticotropin-releasing factor

Cited by 144 publications

References 55 publications

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

Down-Regulation of Hypothalamic Corticotropin-Releasing Hormone Messenger Ribonucleic Acid (mRNA) Precedes Early-Life Experience-Induced Changes in Hippocampal Glucocorticoid Receptor mRNA**This work was supported by NIH Grants NS-28912 and NS-39307.

The role of corticotropin-releasing factor in depression and anxiety disorders

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