title: 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.
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.
authors.affiliation: Department 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
authors.forename: David
authors.initials: D
authors.lastname: Walker
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.forename: Emiliangelo
authors.initials: E
authors.lastname: Ratti
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
authors.forename: David
authors.initials: D
authors.lastname: Trist
authors.forename: Michael
authors.initials: M
authors.lastname: Davis
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005239:Fear; D005260:Female; D008027:Light; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000494:pharmacology; D010775:Photic Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle / Q000187:drug effects*; D000099052:CRF Receptor, Type 1
chemical_list: C541335:GSK876008; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D008747:Methylcellulose; D003346:Corticotropin-Releasing Hormone