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Neuropsychopharmacology. 2009 May;34(6):1533-42. doi: 10.1038/npp.2008.210. Epub 2008 Dec 10.

Differential effects of the CRF-R1 antagonist GSK876008 on fear-potentiated, light- and CRF-enhanced startle suggest preferential involvement in sustained vs phasic threat responses.

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  • 1Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 954 Gatewood Road, Yerkes Neuroscience Bldg, Rm 5214, Atlanta, GA 30329, USA. dlwalke@emory.edu

Abstract

The amplitude of the acoustic startle response is increased when elicited in the presence of brief cues that predict shock (fear-potentiated startle) and also when elicited during sustained exposure to bright light (light-enhanced startle). Although both effects are thought to reflect fear or anxiety, their neuroanatomical substrates differ. Although fear-potentiated startle is disrupted by reversible inactivation of the central nucleus of the amygdala (CeA) but not the closely related bed nucleus of the stria terminalis (BNST), light-enhanced startle is disrupted by BNST inactivation but not by CeA inactivation. Intraventricular infusions of corticotropin-releasing factor (CRF) also increase startle (CRF-enhanced startle) and this effect is mediated by CRF receptors within the BNST, with no involvement of the CeA. Together, these observations suggest that CeA- and BNST-dependent fear and anxiety may be differentially sensitive to CRF receptor blockade. We tested this by orally administering the novel, potent, and selective CRF-R1 antagonist GSK876008 to rats before CRF-enhanced, light-enhanced, or fear-potentiated startle testing. GSK876008 disrupted CRF-enhanced startle with a linear dose-response curve, and light-enhanced startle with a U-shaped dose-response curve, but did not disrupt fear-potentiated startle to a visual stimulus at any dose tested, and even augmented the response in some animals. GSK876008 also disrupted shock-related 'baseline' startle increases, which may have reflected context conditioning (shown elsewhere to also be BNST-dependent). Overall, these results suggest that short-duration CeA-dependent threat responses can be pharmacologically dissociated from longer duration BNST-dependent responses in terms of their sensitivity to CRF1 receptor antagonists.

PMID:
19078950
[PubMed - indexed for MEDLINE]
PMCID:
PMC3586210
Free PMC Article

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