title: Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic stress disorder model.
abstract: Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experience, and presents with characteristic symptoms, such as intrusive memories, a state of hyperarousal, and avoidance, that endure for years. Single-prolonged stress (SPS) is one of the animal models proposed for PTSD. Rats exposed to SPS showed enhanced inhibition of the hypothalamo-pituitary-adrenal (HPA) axis, which has been reliably reproduced in patients with PTSD, and increased expression of glucocorticoid receptor (GR) in the hippocampus. In this study, we characterized further neuroendocrinologic, behavioral and electrophysiological alterations in SPS rats. Plasma corticosterone recovered from an initial increase within a week, and gross histological changes and neuronal cell death were not observed in the hippocampus of the SPS rats. Behavioral analyses revealed that the SPS rats presented enhanced acoustic startle and impaired spatial memory that paralleled the deficits in hippocampal long-term potentiation (LTP) and depression. Contextual fear memory was enhanced in the rats 1 week after SPS exposure, whereas LTP in the amygdala was blunted. Interestingly, blockade of GR activation by administering 17-beta-hydroxy-11-beta-/4-/[methyl]-[1-methylethyl]aminophenyl/-17-alpha-[prop-1-ynyl]estra-4-9-diene-3-one (RU40555), a GR antagonist, prior to SPS exposure prevented potentiation of fear conditioning and impairment of LTP in the CA1 region. Altogether, SPS caused a number of behavioral changes similar to those described in PTSD, which marks SPS as a putative PTSD model. The preventive effects of a GR antagonist suggested that GR activation might play a critical role in producing the altered behavior and neuronal function of SPS rats.
authors.affiliation: Department of Neuropsychiatry, Faculty of Medicine, University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. kkohda@sc.itc.keio.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Kohda
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: A
authors.initials: A
authors.lastname: Hoshino
authors.forename: J
authors.initials: J
authors.lastname: Motohashi
authors.forename: T
authors.initials: T
authors.lastname: Yamaji
authors.forename: S
authors.initials: S
authors.lastname: Morinobu
authors.forename: N
authors.initials: N
authors.lastname: Matsuoka
authors.forename: N
authors.initials: N
authors.lastname: Kato
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001008:Anxiety Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D001362:Avoidance Learning / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D003345:Corticosterone / Q000097:blood* / Q000378:metabolism; D004195:Disease Models, Animal; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D015735:Mifepristone / Q000031:analogs & derivatives / Q000494:pharmacology; D009410:Nerve Degeneration / Q000209:etiology / Q000503:physiopathology; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012021:Reflex, Abnormal / Q000502:physiology; D013216:Reflex, Startle / Q000502:physiology; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism / Q000503:physiopathology*; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D011965:Receptors, Glucocorticoid; C075646:RU 40555; D015735:Mifepristone; D003345:Corticosterone