Facilitation of Conditioned Fear Extinction by Systemic Administration or Intra-Amygdala Infusions of d-Cycloserine as Assessed with Fear-Potentiated Startle in Rats
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NMDA receptor antagonists block conditioned fear extinction when injected systemically and also when infused directly into the amygdala. Here we evaluate the ability of d-cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine-recognition site on the NMDA receptor complex, to facilitate conditioned fear extinction after systemic administration or intra-amygdala infusions. Rats received 10 pairings of a 3.7 sec light and a 0.4 mA footshock (fear conditioning). Fear-potentiated startle (increased startle in the presence vs the absence of the light) was subsequently measured before and after 30, 60, or 90 presentations of the light without shock (extinction training). Thirty non-reinforced light presentations produced modest extinction, and 60 or 90 presentations produced nearly complete extinction (experiment 1). DCS injections (3.25, 15, or 30 mg/kg) before 30 non-reinforced light exposures dose-dependently enhanced extinction (experiment 2) but did not influence fear-potentiated startle in rats that did not receive extinction training (experiment 3). These effects were blocked by HA-966, an antagonist at the glycine-recognition site (experiment 4). Neither DCS nor HA-966 altered fear-potentiated startle when injected before testing (experiment 5). The effect of systemic administration was mimicked by intra-amygdala DCS (10 μg/side) infusions (experiment 6). These results indicate that treatments that promote NMDA receptor activity after either systemic or intra-amygdala administration promote the extinction of conditioned fear.
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Preclinical research has demonstrated that DCS facilitates extinction learning and memory in rodent models.
“Preclinical research has demonstrated that DCS facilitates extinction learning and memory in rodent models (Davis et al, 2006; Ledgerwood et al, 2003; Walker et al, 2002).”
From D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial (2014) · cites this paper as Walker et al, 2002
Weekly dosing administered 90 min before exposure sessions has been effective in multiple animal and human fear extinction studies.
“We chose weekly dosing, administered 90 min before exposure sessions, as this regimen has been effective in multiple animal and human fear extinction studies (Ledgerwood et al, 2003; Ressler et al, 2004; Walker et al, 2002)”
From D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial (2014) · cites this paper as Walker et al, 2002
D-cycloserine (DCS), an NMDA receptor partial agonist, facilitated extinction learning in rats; this finding was replicated in rodents but not replicated using skin conductance and expectancy ratings in humans.
“Walker et al. (64) found that d-cycloserine (DCS), an NMDA receptor partial agonist, facilitated extinction learning in rats; a finding that was later replicated by several other groups employing multiple types of fear learning paradigms in rodents [e.g., Ref. (65)] but not replicated using skin conductance and expectancy ratings in humans (66).”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [64]
Administration of D-cycloserine (DCS), a partial agonist of the NMDA receptor involved in long-term potentiation, facilitates extinction of conditioned fear.
“administration of D-cycloserine (DCS), a partial agonist of the NMDA receptor involved in long-term potentiation (a cellular model of learning), facilitates extinction (e.g., Walker, Ressler, Lu, & Davis, 2002; Ledgerwood, Richardson, & Cranney, 2003).”
From D-cycloserine facilitates context-specific fear extinction learning (2008) · cites this paper as Walker, Ressler, Lu, & Davis, 2002
The DCS dose (15 mg/kg per rat) was chosen on the basis of other behavioral studies.
“The DCS dose (15 mg/kg per rat) was chosen on the basis of the results of other behavioral studies (Ledgerwood et al, 2003(Ledgerwood et al, , 2005;;Walker et al, 2002).”
From Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD (2008) · cites this paper as Walker et al, 2002
Our results are generally in agreement with Walker et al (2002) and Ledgerwood et al (2003) that DCS systemic administration enhanced the extinction of conditioned fear.
“Our results are generally in agreement with the results of Walker et al (2002) and Ledgerwood et al (2003), in which DCS systemic administration enhanced the extinction of conditioned fear.”
From Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD (2008) · cites this paper as Walker et al (2002)
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- Authors
- Walker, D. L., Ressler, K. J., Lu, K.-T., & Davis, M.
- Affiliations
- Emory University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-03-15
- Volume
- 22
- Issue
- 6
- Pages
- 2343-2351
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758267
- OpenAlex
- W1946000001
- Cited by
- 815
- References
- 58
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 8 · 2023: 18 · 2022: 18 · 2021: 22 · 2020: 15 · 2019: 28 · 2018: 29 · 2017: 37 · 2016: 23 · 2015: 47 · 2014: 48 · 2013: 53 · 2012: 54
- FWCI
- 12.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (9876754)
- Woodruff Foundation
- Pfizer
- National Institute of Mental Health (MH59906, MH-57250, R01MH057250, P50MH052384, R01MH059906, P50MH058922, MH58922, MH 47840, MH-52384, R37MH047840, R01MH047840)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- D-cycloserine, fear-potentiated startle, NMDA receptor, glycine site, HA-966, amygdala, fear conditioning, footshock, strychnine-insensitive glycine receptor, NMDA receptor antagonists
- MeSH terms
- Acoustic Stimulation, Amygdala, Animals, Behavior, Animal, Catheterization, Conditioning, Classical, Cycloserine, Dose-Response Relationship, Drug, Electroshock, Extinction, Psychological, Fear, Infusions, Parenteral, Male, Photic Stimulation, Pyrrolidinones, Reflex, Startle, Stereoisomerism, Rats, Sprague-Dawley, Excitatory Amino Acid Agonists, Rats
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