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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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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Corticotropin-releasing factor receptors are preferentially involved in fear-potentiated startle to context but not to discrete fear conditioned stimuli.
“recent findings from Risbrough et al (2009), as well as from our own laboratory (Walker et al, 2009), indicate a similar and, importantly, preferential involvement of CRF receptors in fear-potentiated startle to context but not discrete fear CSs.”
From Phasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety (2010) · cites this paper as Walker et al, 2009
Oral GSK876008, a selective CRF-R1 antagonist, at doses that dose-dependently block CRF-enhanced startle, disrupted light-enhanced startle non-monotonically but did not affect fear-potentiated startle in the same rats.
“using oral administration of the selective CRF-R1 antagonist GSK876008 (Di Fabio et al, 2008), at doses that dose dependently (linear) disrupt CRF-enhanced startle, we also observed a non-monotonic disruption of light-enhanced startle but no disruption of fear-potentiated startle in the same animals at the same doses”
From Phasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety (2010) · cites this paper as Walker et al, 2009
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- Authors
- Walker, D., Yang, Y., Ratti, E., Corsi, M., Trist, D., & Davis, M.
- Affiliations
- Emory University (US)
- GlaxoSmithKline (Italy) (IT)
- Corresponding author
- Walker, David
- Venue
- Neuropsychopharmacology
- Published
- 2008-12-10
- Volume
- 34
- Issue
- 6
- Pages
- 1533-1542
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3586210
- OpenAlex
- W2083022185
- Cited by
- 69
- References
- 48
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 7 · 2015: 1 · 2014: 4 · 2013: 5 · 2012: 2
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (9876754)
- National Institutes of Health (5u19mh069056-10)
- National Institute of Mental Health (MH59906, MH-57250, R01MH057250, R01MH059906, U19-MH069056, MH 47840, R37MH047840, MH069056, R01MH047840)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- corticotropin-releasing factor, fear-potentiated startle, acoustic startle response, central amygdala, bed nucleus of the stria terminalis, threat response, anxiety, contextual conditioning, dose-response relationship
- MeSH terms
- CRF Receptor, Type 1, Analysis of Variance, Animals, Corticotropin-Releasing Hormone, Dose-Response Relationship, Drug, Fear, Female, Light, Male, Methylcellulose, Photic Stimulation, Reflex, Startle, Rats, Sprague-Dawley, Receptors, Corticotropin-Releasing Hormone, Rats
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