The role of glucocorticoid receptors in the induction and prevention of hippocampal abnormalities in an animal model of posttraumatic stress disorder

Araki Motoaki

Fuchikami Manabu

Omura Jun

Miyagi Tatsuhiro

Nagashima Nobuyuki

Okamoto Yasumasa

Morinobu Shigeru

Psychopharmacology

Rationale: Since the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Numerous clinical studies have led to the hypothesis that elevated glucocorticoid levels in response to extreme stress might trigger a pathophysiological cascade which consequently leads to functional and morphological changes in the hippocampus.
Objectives: To elucidate the pathophysiology of PTSD, we examined the alteration of hippocampal gene expression through the glucocorticoid receptor (GR) in the single prolonged stress (SPS) paradigm, a rat model of PTSD.
Methods: We measured nuclear GRs by western blot, and the binding of GR to the promoter of Bcl-2 and Bax genes by chromatin immunoprecipitation-qPCR as well as the expression of these 2 genes by RT-PCR in the hippocampus of SPS rats. In addition, we examined the preventive effects of a GR antagonist on SPS-induced molecular, morphological, and behavioral alterations (hippocampal gene expression of Bcl-2 and Bax, hippocampal apoptosis using TUNEL staining, impaired fear memory extinction (FME) using the contextual fear conditioning paradigm).
Results: Exposure to SPS increased nuclear GR expression and GR binding to Bcl-2 gene, and decreased Bcl-2 mRNA expression. Administration of GR antagonist immediately after SPS prevented activation of the glucocorticoid cascade, hippocampal apoptosis, and impairment FME in SPS rats.
Conclusion: The activation of GRs in response to severe stress may trigger the pathophysiological cascade leading to impaired FME and hippocampal apoptosis. In contrast, administration of GR antagonist could be useful for preventing the development of PTSD.

Animal model

Posttraumatic stress disorder (PTSD)

Glucocorticoid receptor (GR)

GR antagonist

eng

Springer

This is a post-peer-review, pre-copyedit version of an article published in Psychopharmacology. The final authenticated version is available online at: https://doi.org/10.1007/s00213-020-05523-x

This is not the published version. Please cite only the published version. この論文は出版社版ではありません。引用の際には出版社版をご確認、ご利用ください。

[ISSN] 0033-3158

[ISSN] 1432-2072

[DOI] 10.1007/s00213-020-05523-x

[PMID] 32333135

[DOI] https://doi.org/10.1007/s00213-020-05523-x