Effects of single prolonged stress and D-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD.
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.
Yamamoto
Shigeto
S
Department of psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
Morinobu
Shigeru
S
Fuchikami
Manabu
M
Kurata
Akiko
A
Kozuru
Toshiro
T
Yamawaki
Shigeto
S
D000704:Analysis of Variance; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D001522:Behavior, Animal; D003523:Cycloserine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004597:Electroshock / Q000009:adverse effects; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013313:Stress Disorders, Post-Traumatic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013315:Stress, Psychological / Q000150:complications*
D000963:Antimetabolites; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D003523:Cycloserine