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.
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Authors | David Walker, Yong Yang, Emiliangelo Ratti, Mauro Corsi, David Trist, Michael Davis |
Journal | Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
(Neuropsychopharmacology)
Vol. 34
Issue 6
Pg. 1533-42
(May 2009)
ISSN: 1740-634X [Electronic] England |
PMID | 19078950
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- GSK876008
- Receptors, Corticotropin-Releasing Hormone
- CRF receptor type 1
- Methylcellulose
- Corticotropin-Releasing Hormone
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Topics |
- Analysis of Variance
- Animals
- Corticotropin-Releasing Hormone
(metabolism)
- Dose-Response Relationship, Drug
- Fear
- Female
- Light
- Male
- Methylcellulose
(analogs & derivatives, pharmacology)
- Photic Stimulation
- Rats
- Rats, Sprague-Dawley
- Receptors, Corticotropin-Releasing Hormone
(antagonists & inhibitors)
- Reflex, Startle
(drug effects)
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