D-Cycloserine Facilitation of Fear Extinction and Exposure-Based Therapy Might Rely on Lower-Level, Automatic Mechanisms
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Exposure-based therapy, a leading technique in the treatment of a range of anxiety disorders, is facilitated by D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist. This review discusses the potential mechanisms involved in this facilitation and its implications for developing theories of fear conditioning in humans. Basic research in rodents suggests that DCS acts by speeding up extinction. However, several laboratory-based investigations found that DCS had no effect on extinction in humans. This report proposes that these observations can be accounted for by a dual-model theory of fear conditioning in humans that engages two complementary defensive systems: a reflexive lower-order system independent of conscious awareness and a higher-order cognitive system associated with conscious awareness of danger and expectation. The DCS studies in animals seem to have explored lower-order conditioning mechanisms, whereas human studies have explored higher-order cognitive processes. These observations suggest that DCS might act preferentially on lower- rather than higher-order learning. This report presents evidence suggesting that, in humans, DCS might similarly affect lower-order learning during exposure-based therapy and, consequently, might be less effective during cognitive therapy (e.g., cognitive restructuring). Finally, it is recommended that extinction studies using DCS in humans be conducted with fear-relevant stimuli (e.g., snakes), short conditional stimulus-unconditioned stimulus intervals and intense unconditioned stimulus to promote lower-order conditioning processes.
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D-cycloserine is an NMDA receptor partial agonist that promotes NMDA-dependent memory consolidation of therapeutic extinction memory.
“D-cycloserine, an NMDA receptor partial agonist, that promotes NMDA-dependent memory consolidation of therapeutic extinction memory [238–240].”
From Sleep and REM sleep disturbance in the pathophysiology of PTSD: the role of extinction memory (2015) · cites this paper as [240]
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- Authors
- Grillon, C.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Grillon, Christian
- ORCID
- Grillon, Christian
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 66
- Issue
- 7
- Pages
- 636-641
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC2752328
- OpenAlex
- W1988744087
- Cited by
- 80
- References
- 80
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 6 · 2017: 4 · 2016: 7 · 2015: 8 · 2014: 3 · 2013: 8 · 2012: 7
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (Z01MH002798)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Keywords
- D-cycloserine, fear extinction, exposure therapy, NMDA receptor agonist, fear conditioning, dual-process theory, automatic learning, cognitive restructuring, anxiety disorders, snake phobia
- MeSH terms
- Animals, Antimetabolites, Anxiety, Association Learning, Behavior Therapy, Conditioning, Classical, Cycloserine, Extinction, Psychological, Fear, Humans, Models, Psychological
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