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Cited by 224Posttraumatic Stress Disorder ResearchMemory and Neural MechanismsStress Responses and Cortisol

The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index; none of the 41 sources its claims cite is checked for support yet.

Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD

Open access
Yamamoto, Shigeto, Morinobu, Shigeru, Fuchikami, Manabu, Kurata, Akiko, Kozuru, Toshiro, Yamawaki, Shigeto·2008·Neuropsychopharmacology
DOI 10.1038/sj.npp.1301605
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Abstract

Although the impaired extinction of traumatic memory is one of the hallmark symptoms of posttraumatic stress disorder (PTSD), the underlying mechanisms of impaired extinction are unclear and effective pharmacological interventions have not yet been developed. Single prolonged stress (SPS) has been proposed as an animal model of PTSD, since rats subjected to SPS (SPS rats) show enhanced negative feedback of the HPA axis and increased contextual fear, which are characteristics similar to those observed in patients with PTSD. In this study, using SPS rats, we examined (a) the ability of SPS to impair fear extinction, (b) whether D-cycloserine (DCS) can alleviate impaired fear extinction in SPS rats, and (c) the effect of SPS and/or DCS on the levels of N-methyl-D-aspartate (NMDA) receptor subunit mRNAs in the rat hippocampus during extinction training. SPS rats exhibited impaired fear extinction in the contextual fear test, which was alleviated by the repeated administration of DCS. The effect of enhanced extinction, induced by the administration of DCS to SPS rats, was maintained for one week following extinction training. SPS induced significant upregulation of the levels of NMDA receptor subunit mRNAs before and during the period of extinction training, while repeated administration of DCS eliminated the enhanced mRNA levels of NMDARs. Behavioral analyses indicated that SPS is an appropriate animal model of PTSD and that DCS may be effective in the treatment of PTSD. These findings suggest that DCS, irrespective of its mechanistic involvement in the enhancement of fear extinction, may help to reverse hippocampal plasticity, and thus reverse the NMDA compensatory alterations.

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TL;DR

In a rat single prolonged stress (SPS) model of PTSD, SPS impaired contextual fear extinction and upregulated hippocampal NMDA receptor subunit mRNAs, while repeated oral D-cycloserine (DCS) alleviated the extinction deficit and reduced the elevated NMDAR mRNA levels. The authors conclude that SPS is an appropriate PTSD animal model and that DCS may help reverse hippocampal NMDA compensatory alterations, though the mechanism remains unclear.

Key findings

  • SPS rats showed impaired contextual fear extinction: freezing did not differ from Sham on day 1 (t(18)=1.54, p=0.13), but SPS rats froze significantly more on days 2–5 (day 2: t(18)=2.76, p<0.05; day 3: t(18)=3.67, p<0.01; day 4: t(18)=3.63, p<0.01; day 5: t(18)=4.11, p<0.01).
  • Repeated DCS (15 mg/kg oral, daily for 6 days) alleviated impaired fear extinction in SPS rats, and the enhanced extinction was maintained one week after the fifth extinction training without DCS; DCS did not affect consolidation of original fear on day 1.
  • In hippocampus, all four NMDAR subunit mRNAs (NR1, NR2A, NR2B, NR2C) were higher in SPS than Sham before fear conditioning and during extinction training (e.g., day 0: NR1 t(10)=5.04, p<0.01; NR2A t(10)=2.93, p<0.05; NR2B t(10)=3.68, p<0.01; NR2C t(10)=5.11, p<0.01; day 4 all p<0.01).
  • Repeated DCS eliminated the enhanced NMDAR mRNA levels in SPS rats; Experiment 4 found significant stress×drug interactions for NR1, NR2A, NR2B, and NR2C, with the reduction most consistent for the SPS group, and the discussion specifically notes DCS eliminated enhanced NR2A and NR2B mRNA levels in SPS rats.

Methods

  • Male Sprague-Dawley rats weighing 300–350 g were used; total N=176 (Experiment 1: N=20; Experiment 2: N=76; Experiment 3: N=44; Experiment 4: N=36). SPS consisted of 2 h restraint, 20 min forced swim at 24°C, ether anesthesia, then 7 days undisturbed in home cage.
  • Contextual fear conditioning used two 4-s, 0.8-mA footshocks; extinction training was 10 min of context exposure without footshock on five consecutive days. Freezing was scored blindly, with interrater reliability r=0.96.
  • DCS was administered orally in drinking water at a target dose of 15 mg/kg/day for 6 days (Experiment 2A) or 5 days (Experiment 4). Hippocampal NMDAR subunit mRNAs were measured by real-time quantitative PCR relative to GAPDH; analyses used ANOVA, t-tests, and Tukey post hoc tests, with significance at p<0.05.

Limitations

  • Stated: oral DCS administration meant the exact amount consumed by each rat daily could not be accurately confirmed, so the DCS concentration could only be assumed to be approximately 15 mg/kg.
  • Stated: the study did not evaluate NMDAR protein levels, NMDAR phosphorylation, or NMDAR-mediated intracellular signal transduction in the hippocampus.
  • Stated: enhanced hippocampal NMDA receptor expression does not necessarily occur in other brain regions, could be a consequence rather than a causative factor of impaired fear extinction, and other regions such as the amygdala and medial prefrontal cortex may be involved. Evident: DCS did not enhance extinction in Sham rats, which the authors suggest may reflect a floor effect from the 10-min context exposure or inadequate DCS consumption, and the mechanism by which DCS alleviates extinction impairment was not clarified.

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Integrity signals

Registry

Crossref · 10.1038/sj.npp.1301605

Cites

39 of 39 references verified0 citation errors · 0 not checkable

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Claims the paper makes

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Show all 48 claims

  • The quote only partly states this claim. 2
  • Probably not a substantial claim. 23
  • It may state two separate claims as one. 8
28 of 28

  • The paper relies on this without support.

    DCS enhances excitatory neurotransmission mediated by NMDA receptors by binding to the strychnine-insensitive glycine recognition site of the NMDA receptor complex, without inducing neurotoxicity.

    “DCS enhances excitatory neurotransmission mediated by NMDA receptors, by binding to the strychnine-insensitive glycine recognition site of the NMDA receptor complex, without inducing neurotoxicity.”

  • The paper relies on this without support.

    The levels of NMDAR subunit mRNAs measured by RT-PCR reflect hippocampal NMDA receptor expression or function.

    “To elucidate whether the hippocampal glutamatergic systems are involved in fear extinction, we used RT-PCR to measure alterations in NMDAR mRNA levels in the hippocampus during extinction training (Experiment 3).”

  • The authors state this as an assumption.

    The concentration of DCS could only be assumed to be approximately 15 mg/kg.

    “Hence, it should be noted that the concentration of DCS could only be assumed to be approximately 15 mg/kg.”

  • The paper relies on this without support.

    This is the first study indicating the efficacy of DCS upon fear extinction in a conditioned stress model of PTSD.

    “This is the first study indicating the efficacy of DCS upon fear extinction in a conditioned stress model of PTSD.”

  • The paper relies on this without support.

    Little has been reported previously concerning the effects of DCS upon fear consolidation.

    “To our knowledge, little has been reported previously concerning the effects of DCS upon fear consolidation.”

  • The paper relies on this without support.

    The initial level of freezing is critical in the assessment of contextual fear extinction by DCS.

    “As mentioned above, the initial level of freezing is also critical in the assessment of contextual fear extinction by DCS.”
6 of 6

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Experiment 2B ANOVA degrees of freedom conflict with group sizes

    Major

    Figure 4 reports nine rats in each of four groups, or 36 rats total, which would give 32 between-subject degrees of freedom. The reported ANOVA uses 16, consistent with only 20 rats.

  • Experiment 2A ANOVA degrees of freedom conflict with group sizes

    Minor

    Figure 3 reports four groups of 10 rats, or 40 rats total; its day-1 ANOVA also uses a residual degree of freedom of 36. The reported three-way repeated-measures ANOVA instead uses 18 between-subject degrees of freedom, consistent with only 20 rats.

  • Rat weights are given in both grams and milligrams

    Minor

    The animals are described as weighing 300-350 g, but the dosing calculation gives an average rat weight of 330 mg. These values differ by a factor of 1,000.

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Metadata

Authors
Yamamoto, S., Morinobu, S., Fuchikami, M., Kurata, A., Kozuru, T., & Yamawaki, S.
Affiliations
Hiroshima University (JP)
Corresponding author
Yamawaki, Shigeto
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2007-10-24
Volume
33
Issue
9
Pages
2108-2116
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/sj.npp.1301605
OpenAlex
W2060475258
Cited by
224
References
39
Citations by year
2026: 2 · 2025: 9 · 2024: 3 · 2023: 11 · 2022: 7 · 2021: 11 · 2020: 15 · 2019: 13 · 2018: 23 · 2017: 12 · 2016: 13 · 2015: 16 · 2014: 16 · 2013: 18 · 2012: 17
FWCI
9.10
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
  • Hiroshima University Institutional Repository (submittedVersion, other-oa)
  • Hiroshima University Acedemic Information Repository (Hiroshima University) (submittedVersion)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
post-traumatic stress disorder, single prolonged stress, D-cycloserine, fear extinction, contextual fear, NMDA receptor subunits, hippocampus, hippocampal plasticity, hypothalamic-pituitary-adrenal axis, animal model of PTSD
MeSH terms
Analysis of Variance, Animals, Antimetabolites, Behavior, Animal, Cycloserine, Disease Models, Animal, Electroshock, Extinction, Psychological, Fear, Gene Expression Regulation, Hippocampus, Male, RNA, Messenger, Stress Disorders, Post-Traumatic, Stress, Psychological, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Rats

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