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Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD
Open accessAbstract
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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30 Own result · 24 Not checked yet · 12 Own method · 8 Own interpretation · 1 Supported · 1 No basis given
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In the paper
“In addition, SPS rats also exhibit a sustained exaggeration of the acoustic startle response (Khan and Liberzon, 2004).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > INTRODUCTION
What the sources say
- Supportedcites Khan and Liberzon, 2004 source
The Discussion explicitly states that SPS produced a sustained enhancement of the acoustic startle response. The Results report a significantly higher response in SPS rats than controls on day 17, in the 108 dB condition. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SPS rats exhibited impaired fear extinction in the contextual fear test, which was alleviated by the repeated administration of DCS.”
- Also stated in: § Experiment 1: Influence of SPS on Fear Extinction · plain
“During repeated context exposure, however, a significant difference in the freezing responses between the two groups appeared on day 2, and significant differences persisted until day 5 (day 2: t(18) ¼ 2.76; po0.05, day 3: t(18) ¼ 3.67; po0.01, day 4: t(18) ¼ 3.63; po0.01, day 5: t(18) ¼ 4.11; po0.01) (Figure 2).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Experiment 1: Influence of SPS on Fear Extinction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
- Also stated in: § Experiment 3: Measurement of the mRNA Levels of NMDARs in the Hippocampus During Extinction Training · boosted
“Collectively, our comparison of NMDAR expression in the hippocampus between the SPS and Sham groups demonstrated that the levels of all four NMDAR subunits in the SPS group were significantly higher than those in the Sham group, both before and during the entire period of extinction training.”
- Also stated in: § Experiment 3: Measurement of the mRNA Levels of NMDARs in the Hippocampus During Extinction Training · plain
“before fear conditioning, we observed that the levels of all NMDAR subunit mRNAs in the SPS group were higher than those in the Sham group (NR 1: t(10) ¼ 5.04; po0.01,NR2A: t(10) ¼ 2.93; po0.05,NR2B: t(10) ¼ 3.68; po0.01,NR2C: t(10) ¼ 5.11; po0.01).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Abstract
boosteddirectn = 44- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Experiment 3: Measurement of the mRNA Levels of NMDARs in the Hippocampus During Extinction Training · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while repeated administration of DCS eliminated the enhanced mRNA levels of NMDARs.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effect of enhanced extinction, induced by the administration of DCS to SPS rats, was maintained for one week following extinction training.”
- Also stated in: § Experiment 2: Effects of DCS Administration on Fear Extinction · plain
“Both of the groups administered with DCS exhibited less freezing on day 12 as compared to day 5.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Experiment 2: Effects of DCS Administration on Fear Extinction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SPS rats exhibited impaired fear extinction in the contextual fear test, which was alleviated by the repeated administration of DCS.”
- Also stated in: § Experiment 2: Effects of DCS Administration on Fear Extinction · boosted
“In Experiment 2A, three-way repeated measures ANOVA demonstrated significant main effects of day (F(4, 72) ¼ 105.39, po0.01), stress (F(1, 18) ¼ 16.41, po0.01), drug (F(1, 18) ¼ 9.81, po0.01), and significant interactions between stress and drug (F(1, 18) ¼ 5.71, po0.05), and between stress and day (F(4, 72) ¼ 2.71, po0.05).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Experiment 2: Effects of DCS Administration on Fear Extinction · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, in comparing data across the experimental timepoints, we have demonstrated that extinction training affected the levels of all NMDAR subunit mRNAs in the hippocampus.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Experiment 3: Measurement of the mRNA Levels of NMDARs in the Hippocampus During Extinction Training
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The principal findings of this study are that (1) SPS induced marked impairment of contextual fear extinction in the rats”
- Also stated in: § DISCUSSION · plain
“In Experiment 1, SPS rats showed significant impairment of contextual fear extinction as compared with Sham rats.”
- Also stated in: § DISCUSSION · plain
“However, on days 2-5, the SPS group showed impaired extinction compared to the Sham group.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
plaindirectn = 10- Asserted: passes — The authors put it forward as true.
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- Also stated in: § DISCUSSION · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and a significant interaction between stress and drug (F(1, 32) ¼ 8.47, po0.01)”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Experiment 4: Effects of Repeated DCS Administration on NMDAR mRNA Levels in the Hippocampus During Extinction Training
plaincorrelationaln = 36- Asserted: passes — The authors put it forward as true.
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In the paper
“For NR2B mRNA levels, two-way ANOVA showed a significant effect of drug (F(1, 32) ¼ 31.91,po0.01)”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Experiment 4: Effects of Repeated DCS Administration on NMDAR mRNA Levels in the Hippocampus During Extinction Training
plaincorrelationaln = 36- Asserted: passes — The authors put it forward as true.
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- The quote only partly states this claim. 2
- Probably not a substantial claim. 23
- It may state two separate claims as one. 8
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In the paper
“in Experiment 4, we also found that the administration of DCS eliminated the enhanced mRNA levels of NR2A and NR2B in SPS rats.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We also verified that the three rats in any one cage consumed approximately 120 ml of Milli-Q water, with or without DCS.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Drug Treatment
plainn = 3- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
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In the paper
“All standards and samples were assayed in triplicate.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Measurement of the Levels of NMDARs in the Hippocampus by Real-Time Quantitative Polymerase Chain Reaction (RT-PCR)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Rats showed freezing responses similarly to comparable rats in Experiment 2A.This was despite independent sets of rats being used for each experiment.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Experiment 4: Effects of Repeated DCS Administration on NMDAR mRNA Levels in the Hippocampus During Extinction Training
plainn = 36- Asserted: passes — The authors put it forward as true.
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In the paper
“Third, it should be noted that because there is enhanced NMDA receptor expression in the hippocampus, this does not mean that the same is happening in other areas of brain.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, using this methodology it was not possible to accurately confirm the amount of Milli-Q water consumed by each rat daily.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Drug Treatment
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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Probably not a substantial claim.
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In the paper
“Second, we did not evaluate changes in the protein level of NMDARs, the extent of NMDAR phosphorylation, or intracellular signal transduction mediated by NMDARs in the hippocampus.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Subsequently, DCS was found to enhance extinction, rather than consolidation of fear.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“The interrater reliability between the two scorers was high (r ¼ 0.96).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Contextual Fear Conditioning and Extinction Training
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For example, Szapiro et al (2003), using a step-down avoidance paradigm, found that intrahippocampal infusions (CA1 region) of the NMDA receptor antagonist, AP5, immediately after the first of four daily extinction exposures, produced a lasting impairment that persisted even with additional extinction training without infusions.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > INTRODUCTION
What the sources say
- Not checked yetcites Szapiro et al, 2003
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although the neurocircuitry mechanism of contextual fear extinction is not fully understood, brain regions such as the hippocampus, amygdala, and prefrontal cortex are involved in the memory extinction (Sotres-Bayon et al, 2004, 2006).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > INTRODUCTION
What the sources say
- Not checked yetcites Sotres-Bayon et al, 2004, 2006
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The levels of NMDAR subunit mRNAs measured by RT-PCR reflect hippocampal NMDA receptor expression or function.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal procedures were conducted in strict accordance with the Hiroshima University School of Medicine Animal Care Committee Guiding Principles”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Animals were randomly assigned to two groups (SPS, Sham).”
- Also stated in: § Drug Treatment · plain
“Animals were randomly assigned to four groups (SPS, SPS + DCS, Sham, Sham + DCS).”
- Also stated in: § Measurement of the Levels of NMDARs in the Hippocampus by Real-Time Quantitative Polymerase Chain Reaction (RT-PCR) · plain
“Animals were randomly assigned to two groups (SPS, Sham), and were sacrificed by decapitation at the indicated time on day 0 (before fear conditioning), on day 1 (after the first context exposure), or on day 4 (after the fourth context exposure).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Contextual Fear Conditioning and Extinction Training
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Probably not a substantial claim.
- Also stated in: § Drug Treatment · plain
None of the sources cited for this claim have been checked yet.
In the paper
“Studies reported by Parnas et al (2005) and Quartermain et al (1994) described the multiple administration of DCS before fear conditioning or the maze learning test, respectively (ie preadministration of DCS).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
- Not checked yetcites Parnas et al (2005)
- Not checked yetcites Quartermain et al (1994) source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The hippocampus has strong reciprocal connections with the mPFC and the amygdala; these three brain regions seem to interactively coordinate the encoding and expression of fear extinction (Sotres-Bayon et al, 2006).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
- Not checked yetcites Sotres-Bayon et al, 2006 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“On the other hand, chronic preexposure of DCS has been reported to eliminate effects upon fear extinction (Parnas et al, 2005).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
- Not checked yetcites Parnas et al, 2005
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For example, Corcoran et al (2005) have demonstrated that muscimol inactivation of the dorsal hippocampus reduced the rate of extinction and prevented the context dependency of extinction.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
- Not checked yetcites Corcoran et al (2005)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Previous studies by this group indicated that treating the dorsal hippocampus with muscimol produced selective impairment in the context specificity of extinction (Corcoran and Maren, 2001).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
- Not checked yetcites Corcoran and Maren, 2001
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“More recently, Heldt et al (2007) demonstrated that the hippocampal expression of BDNF is required for the neural plasticity underlying the acquisition or consolidation of extinction memories.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
- Not checked yetcites Heldt et al (2007) source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Heresco-Levy et al (2002) used daily chronic dosing without exposure therapy, while Hofmann et al (2006) and Ressler et al (2004) used acute dosing with exposure therapy.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In addition, Fischer et al (2004) have shown that structural plasticity involving actin rearrangement within dorsal hippocampus is required for contextual fear extinction.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
- Not checked yetcites Fischer et al (2004)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, we cannot rule out the possibility of the involvement of other brain regions in fear extinction as described above.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For example, Rouaud and Billard (2003) showed that DCS facilitated NMDAR-mediated signal transduction and synaptic plasticity in the CA1 field of rat hippocampal slices.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
- Not checked yetcites Rouaud and Billard (2003)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, we did not clarify the mechanism by which DCS alleviated the impairment of extinction in SPS rats.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, it is plausible that the enhanced NMDA receptor expression observed in the hippocampus could be a consequence, but not a causative factor, of impaired fear extinction.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“Similarly, Quartermain et al (1994) reported that chronic preexposure to DCS for 15 days led to a significant decrease in the effect of DCS upon the maze learning test (Quartermain et al, 1994).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
What the sources say
- Not checked yetcites Quartermain et al (1994) source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“SPS exposure also results in impaired extinction of contextual fear (Yamamoto et al, 2007).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Yamamoto et al, 2007
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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Experiment 2: Effects of DCS Administration on Fear Extinction
“Three-way repeated measures ANOVA revealed significant main effects associated with day (F(1, 16) ¼ 20.71, po0.01), stress (F(1, 16) ¼ 21.39, po0.01) and drug (F(1, 16) ¼ 15.6, po0.01).”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
“Figure: 4 Figure 4 Figure 4 Effects of repeated DCS administration upon fear extinction a week after extinction training.Data are expressed as mean ± SEM of nine rats per group.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Experiment 2: Effects of DCS Administration on Fear Extinction
“In Experiment 2A, three-way repeated measures ANOVA demonstrated significant main effects of day (F(4, 72) ¼ 105.39, po0.01), stress (F(1, 18) ¼ 16.41, po0.01), drug (F(1, 18) ¼ 9.81, po0.01)”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > DISCUSSION
“Figure: 3 Figure 3 Figure3Effects of repeated DCS administration on fear extinction.Data are expressed as mean±SEM of 10 rats per group.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Animals
“Male Sprague-Dawley rats weighing between 300 and 350 g (Japan Charles River, Yokohama, Japan) were used in our studies.”
§ Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD > Drug Treatment
“Thus, the average weight of a rat (330 mg), was used to calculate the appropriate dose of DCS”
Citations
Cites
Diagnostic and Statistical Manual of Mental Disorders
Williams, J. B. W., & First, M. B. (2013) · Oxford University Press eBooks · doi:10.1093/acrefore/9780199975839.013.104 · Cited by 109,845
Rauch, S. L., Shin, L. M., & Phelps, E. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.06.004 · Cited by 1,397
Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., Hodges, L., & Davis, M. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.11.1136 · Cited by 1,063
Walker, D. L., Ressler, K. J., Lu, K.-T., & Davis, M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-06-02343.2002 · Cited by 815
Heldt, S. A., Stanek, L., Chhatwal, J. P., & Ressler, K. J. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001957 · Cited by 684
Prefrontal mechanisms in extinction of conditioned fear
Quirk, G. J., Garcia, R., & González-Lima, F. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.010 · Cited by 682
Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala
Falls, W., Miserendino, M., & Davis, M. (1992) · The Journal of Neuroscience · doi:10.1523/jneurosci.12-03-00854.1992 · Cited by 673
Fear extinction in rats: Implications for human brain imaging and anxiety disorders
Milad, M. R., Rauch, S. L., Pitman, R. K., & Quirk, G. J. (2006) · Biological Psychology · doi:10.1016/j.biopsycho.2006.01.008 · Cited by 597 · cited 1×
“…such as reexperiencing of trauma in PTSD, since extinction is defined as a reduction in conditioned fear response when the conditioned stimulus is repeatedly presented in the absence of an unconditioned stimulus (Milad et al, 2006; Quirk et al, 2006; Rauch et al, 2006; Rothbaum and Davis, 2003).”
BackgroundAugmentation of Exposure Therapy With D-Cycloserine for Social Anxiety Disorder
Hofmann, S. G., Meuret, A. E., Smits, J. A. J., Simon, N. M., Pollack, M. H., Eisenmenger, K., Shiekh, M., & Otto, M. W. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.3.298 · Cited by 560 · cited 4×
“(2004) and Hofmann et al. (2006) have recently reported that DCS facilitates fear extinction in patients with anxiety disorders.”
BackgroundMethodInfluentialStress-restress: Effects on ACTH and fast feedback
Liberzon, I., Krstov, M., & Young, E. A. (1997) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(97)00044-9 · Cited by 556
Cited by
Sorted by citations
Biological studies of post-traumatic stress disorder
Pitman, R. K., Rasmusson, A. M., Koenen, K. C., Shin, L. M., Orr, S. P., Gilbertson, M. W., Milad, M. R., & Liberzon, I. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3339 · Cited by 1,529
Neuronal circuits of fear extinction
Herry, C., Ferraguti, F., Singewald, N., Letzkus, J. J., Ehrlich, I., & Lüthi, A. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07101.x · Cited by 484
Maren, S., & Holmes, A. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.180 · Cited by 412
Singewald, N., Schmuckermair, C., Whittle, N., Holmes, A., & Ressler, K. J. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.12.004 · Cited by 390
Single prolonged stress: toward an animal model of posttraumatic stress disorder
Yamamoto, S., Morinobu, S., Takei, S., Fuchikami, M., Matsuki, A., Yamawaki, S., & Liberzon, I. (2009) · Depression and Anxiety · doi:10.1002/da.20629 · Cited by 316
Self-citation
Metadata
- Authors
- Yamamoto, S., Morinobu, S., Fuchikami, M., Kurata, A., Kozuru, T., & Yamawaki, S.
- Affiliations
- Hiroshima University (JP)
- Corresponding author
- Yamawaki, Shigeto
- Venue
- Neuropsychopharmacology
- Published
- 2007-10-24
- Volume
- 33
- Issue
- 9
- Pages
- 2108-2116
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- 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
- bronze
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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Statistics and arithmetic are recomputed, not judged.
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