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

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.

Previous Stress Attenuates the Susceptibility to Midazolam's Disruptive Effect on Fear Memory Reconsolidation: Influence of Pre-Reactivation D-Cycloserine Administration

“…A growing body of data supports the view that DCS facilitates the formation of extinction memory (Ledgerwood et al, 2003;Walker et al, 2002;Yamamoto et al, 2008); moreover, DCS facilitates learning and memory using a variety of learning paradigms in diverse animal species (Land and Riccio, 1999;Matsuoka and Aigner, 1996;Monahan et al, 1989;Pitkänen et al, 1995;Pussinen et al, 1997;Quartermain et al, 1994;Thompson et al, 1992). Our findings showed that DCS administration did not affect freezing during reactivation under the present treatment protocol as comparable levels of fear were observed between DCS-and SAL-treated animals, regardless whether animals were subjected to a threatening event before learning.…”

“…We have reported that the facilitating effect of stress on conditioned freezing was observed on the second 5 min period of a 10 min testing session using a similar fear conditioning paradigm and stressor to those used in this study. This indicates that the enhanced fear is likely to be caused by the attenuation of an extinction process rather than an increased fear acquisition (Rodríguez Manzanares et al, 2005;Yamamoto et al, 2008). In fact, resistance to extinction could reflect the strength of the learning process (Myers and Davis, 2002); therefore, it seems possible that the absence of difference in freezing behavior between control and stressed rats during reactivation be the result of the shorter retrieval session used in this study.…”

“…Apparently, this finding is contradictory to the lack of effect on memory reconsolidation of stressed rats after MDZ administration observed in the current research. It is noteworthy that stress experience strengthened fear memory and this influence is revealed by two main effects: (a) enhanced fear retention or fear expression as previously demonstrated using the SPS (Takahashi et al, 2007;Kohda et al, 2007) and/or (b) the impairment of fear extinction or the resistance to extinguish (Rodríguez Manzanares et al, 2005;Akirav and Maroun, 2007;Yamamoto et al, 2008). In contrast, Zhang and Cranney (2008) found no increase of fear expression and no alteration of extinction rate in the rats subjected to modified SPS, despite increased anxiety as evidenced in an elevated plus-maze test.…”

Changes in 5-HT1A receptor in the dorsal raphe nucleus in a rat model of post-traumatic stress disorder

“…It was reported that SPS, a putative PTSD animal model, presents behavioral alterations resembling and shows the most consistent neuroendocrinologic characteristics with PTSD patients (35,36). Rats exposed to SPS exhibited enhanced inhibition of the HPA system and alteration in the glucocorticoid/mineralocorticoid receptor.…”

d-cycloserine in the basolateral amygdala prevents extinction and enhances reconsolidation of odor-reward associative learning in rats

“…Previous literature has mainly examined the effects of DCS on contextual or auditory conditioned fear, indicating that systemic and intra-BLA administrations of DCS may potentiate both extinction and reconsolidation (Ledgerwood, Richardson & Cranney, 2003;Ledgerwood et al, 2005;Lee et al, 2006;Toth et al, 2012;Walker, Ressler, Lu & Davis, 2002;Yamada, Zushida, Wada & Sekiguchi, 2009;Yamamoto et al, 2008). Also, DCS in the BLA facilitated the extinction of contextual fear with no effect on the extinction of conditioned taste aversion (Akirav, Segev, Motanis, & Maroun, 2009).…”