There is extensive evidence that brain neurons containing norepinephrine (NE) and corticotropin-releasing factor (CRF) are activated during stress, that activations of these two neurotransmitters are related to stress-related behavioral responses, and that both may be involved in anxiety and depression. Interactions between neurons containing NE and CRF are extensive. Noradrenergic neurons are among those that can stimulate CRF-containing neurons initiating the activation of the hypothalamo-pituitary-adrenal (HPA) axis, critical in the stress response, while other CRF-neurons in the brain may also be affected. Intracerebral administration of CRF activates NE neurons, especially those with cell bodies in the locus coeruleus (LC). Thus it has been proposed that depression may result from a sensitization of these interactions, creating a """"""""feed forward"""""""" mechanism in which each system activates the other. The brain circuits involved may include the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the lateral septum, in addition to the hypothalamic paraventricular nucleus and the LC. The research proposed aims to focus our previous work on CRF and NE interactions to elucidate details of the adaptations to chronic stress that may provide insight into the mechanisms involved in anxiety disorders and depression.
The specific aim of this proposal is to determine whether or not such a feed-forward hypothesis is reasonable, by examining the adaptation in the behavioral, noradrenergic and HPA responses to acute stress and CRF in chronically stressed animals. ? This will be done by assessing the behavioral responses and NE release and plasma corticosterone in response to acute stress, and comparing these to the responses to intracerebral injection of CRF.
The specific aims will be to determine the neurochemical (NE) and behavioral responses of chronically stressed rats to acute footshock and to CRF injected locally into the LC. Two different chronic stressor paradigms will be used: footshock and exposure to the odor of a predator (fox urine). The NE responses will be determined initially by measuring NE metabolites, but this will be followed by studies using in vivo chronoamperometry and microdialysis in rats. We will determine and compare the subtype(s) of CRF receptor involved in the responses to footshock and to CRF administration. The results should establish a model and indicate the nature of the cerebral structures involved, so that we can subsequently test the feed-forward hypothesis ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH050947-27
Application #
7531500
Study Section
Special Emphasis Panel (ZRG1-NMB (03))
Program Officer
Winsky, Lois M
Project Start
1995-08-01
Project End
2011-07-31
Budget Start
2008-02-01
Budget End
2011-07-31
Support Year
27
Fiscal Year
2008
Total Cost
$259,832
Indirect Cost
Name
University of Hawaii
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Blotta, Simona; Jakubikova, Jana; Calimeri, Teresa et al. (2012) Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma. Blood 120:5002-13
Lin, Yan; Sarfraz, Yasmeen; Jensen, Ashley et al. (2011) Participation of brainstem monoaminergic nuclei in behavioral depression. Pharmacol Biochem Behav 100:330-9
Lin, Yan; Quartermain, David; Dunn, Adrian J et al. (2008) Possible dopaminergic stimulation of locus coeruleus alpha1-adrenoceptors involved in behavioral activation. Synapse 62:516-23
Dunn, Adrian J; Swiergiel, Artur H (2008) Effects of acute and chronic stressors and CRF in rat and mouse tests for depression. Ann N Y Acad Sci 1148:118-26
Dunn, Adrian J; Swiergiel, Artur H (2008) The role of corticotropin-releasing factor and noradrenaline in stress-related responses, and the inter-relationships between the two systems. Eur J Pharmacol 583:186-93
Swiergiel, Artur H; Leskov, Igor L; Dunn, Adrian J (2008) Effects of chronic and acute stressors and CRF on depression-like behavior in mice. Behav Brain Res 186:32-40
Swiergiel, Artur H; Li, Yaohui; Wei, Zhong You et al. (2008) Effects of chlordiazepoxide on footshock- and corticotropin-releasing factor-induced increases in cortical and hypothalamic norepinephrine secretion in rats. Neurochem Int 52:1220-5
Swiergiel, Artur H; Zhou, Yueping; Dunn, Adrian J (2007) Effects of chronic footshock, restraint and corticotropin-releasing factor on freezing, ultrasonic vocalization and forced swim behavior in rats. Behav Brain Res 183:178-87
Lenard, Natalie R; Dunn, Adrian J (2005) Potential role for nonesterified fatty acids in beta-adrenoceptor-induced increases in brain tryptophan. Neurochem Int 46:179-87
Lenard, Natalie R; Dunn, Adrian J (2004) Increased insulin is not required for beta2-adrenoceptor-induced increases in mouse brain tryptophan. Eur J Pharmacol 497:105-10

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