Corticotropin-releasing factor (CRF) and serotonin (5-HT) systems have been independently implicated in stress-related psychiatric disorders. We demonstrate potent effects of CRF on forebrain 5-HT release and activity of putative 5-HT dorsal raphe nucleus (DRN) neurons. Taken with findings of CRF innervation and expression of CRF receptors in the DRN, these results suggest that endogenous CRF acts within the DRN to regulate forebrain 5-HT function. The following AIMS test this hypothesis by characterizing CRF-5-HT interactions at an ultrastructural, electrophysiological and neurochemical level, identifying conditions that engage these interactions, and determining whether CRF effects within the DRN play a role in a behavior associated with depression. 1) Characterize and quantify CRF effects on extracellular 5-HT levels in terminal regions and DRN neuronal activity. Dose-response curves will be generated for CRF effects (administered i.c.v. or intraraphe) on 5-HT release in lateral septum, amygdala and cortex and DRN neuronal activity. The efficacy of CRF antagonists (administered i.c.v., systemically or intraraphe) to prevent these effects will be determined.
This AIM will reveal whether CRF acts directly within the DRN to alter forebrain 5-HT release, whether effects on 5-HT release are regionally specific and the CRF receptor subtype involved; 2) Identify physiological conditions during which endogenous CRF impacts on DRN-5-HT systems. The ability of CRF antagonists (administered i.c.v. or intraraphe) to prevent changes in forebrain 5-HT release elicited by different challenges will be determined.
This AIM will reveal conditions during which CRF-5-HT interactions are engaged; 3) Characterize cellular substrates for CRF-5-HT interactions in the DRN and identify CRF afferents to the DRN. Interactions between CRF terminals and 5-HT processes in the DRN will be visualized at the ultrastructural level using dual label immunohistochemistry and electron microscopy. Neuronal tract tracing will be used to identify CRF afferents to the DRN.
This AIM will reveal potential cellular mechanisms underlying CRF-5-HT interactions and provide a map detailing how CRF systems link to the DRN; 4) Elucidate the role of CRF-5-HT interactions in a behavior associated with depression. The hypothesis that CRF release in the DRN and subsequent inhibition of 5-HT forebrain release underlie behavioral immobility associated with swim stress will be tested. The effects of CRF or CRF antagonists (administered i.c.v. or intraraphe) on behavior in the forced swim test will be determined.
This AIM will reveal potential pathophysiological consequences of CRF-5HT interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH058250-04
Application #
6293060
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Winsky, Lois M
Project Start
1998-12-01
Project End
2001-11-30
Budget Start
2000-02-01
Budget End
2000-11-30
Support Year
4
Fiscal Year
2000
Total Cost
$266,509
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hwa, Lara S; Shimamoto, Akiko; Kayyali, Tala et al. (2016) Dissociation of ?-opioid receptor and CRF-R1 antagonist effects on escalated ethanol consumption and mPFC serotonin in C57BL/6J mice. Addict Biol 21:111-24
Wood, Susan K; Wood, Christopher S; Lombard, Calliandra M et al. (2015) Inflammatory Factors Mediate Vulnerability to a Social Stress-Induced Depressive-like Phenotype in Passive Coping Rats. Biol Psychiatry 78:38-48
Snyder, Kevin P; Hill-Smith, Tiffany E; Lucki, Irwin et al. (2015) Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History. Neuropsychopharmacology 40:2517-25
Wood, Susan K; Zhang, Xiao-Yan; Reyes, Beverly A S et al. (2013) Cellular adaptations of dorsal raphe serotonin neurons associated with the development of active coping in response to social stress. Biol Psychiatry 73:1087-94
Wood, Susan K; McFadden, Kile V; Grigoriadis, Dimitri et al. (2012) Depressive and cardiovascular disease comorbidity in a rat model of social stress: a putative role for corticotropin-releasing factor. Psychopharmacology (Berl) 222:325-36
Waselus, Maria; Valentino, Rita J; Van Bockstaele, Elisabeth J (2011) Collateralized dorsal raphe nucleus projections: a mechanism for the integration of diverse functions during stress. J Chem Neuroanat 41:266-80
Bingham, Brian; McFadden, Kile; Zhang, Xiaoyan et al. (2011) Early adolescence as a critical window during which social stress distinctly alters behavior and brain norepinephrine activity. Neuropsychopharmacology 36:896-909
Nazzaro, Cristiano; Barbieri, Mario; Varani, Katia et al. (2010) Swim stress enhances nociceptin/orphanin FQ-induced inhibition of rat dorsal raphe nucleus activity in vivo and in vitro: role of corticotropin releasing factor. Neuropharmacology 58:457-64
Valentino, Rita J; Lucki, Irwin; Van Bockstaele, Elisabeth (2010) Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction. Brain Res 1314:29-37
Waselus, Maria; Nazzaro, Cristiano; Valentino, Rita J et al. (2009) Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus. Biol Psychiatry 66:76-83

Showing the most recent 10 out of 14 publications