ORIGINAL ARTICLES Blunted HPA Axis Response to Stress Influences Susceptibility to Posttraumatic Stress Response in Rats Hagit Cohen, Joseph Zohar, Yori Gidron, Michael A. Matar, Dana Belkind, Uri Loewenthal, Nitsan Kozlovsky, and Zeev Kaplan Background: Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. Method: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. Results: Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague–Dawley rats, with only minor corticosterone increases following stress. Prevalence of EBR was 50% among Lewis rats compared with 10% of Fischer F344 and 25% of Sprague–Dawley rats. Administering corticosterone 1 hour before stress exposure reduced the prevalence of EBR from 50% to 8% in the Lewis rats. Conclusions: These results suggest that a blunted HPA response to stress may play a causal role in this model of PTSD and that this susceptibility may be prevented by administration of cortisol before stress exposure. Key Words: Animal model, anxiety, corticosterone, HPA axis, im- mune system, maladapted, pro-inflammatory cytokines, posttrau- matic stress disorder, well-adapted T he response of an individual to stress is characterized by both emotional and physical manifestations, involving the activation of various physiological systems (McEwen 2001). The consequences of this “stress response” are generally adaptive in the short run, representing a homeostatic reaction but in the long run can cause dysregulation of the complex cascade of mechanisms responsible for maintenance of homeostasis allostasis (McEwen 2002). When the dysregulation is not over- come by the organism to reestablish and maintain homeostasis, long-term changes can occur, exemplified in human subjects by posttraumatic stress disorder (PTSD; American Psychiatric Asso- ciation 1994). Exposure to stress or a threat to homeostasis triggers activa- tion of the parvicellular neurons of the paraventricular nucleus (PVN) in the hypothalamus to release corticotropin-releasing factor (CRF) and vasopressin. These hormones stimulate synthe- sis of polypeptide precursor pro-opiomelanocortin (POMC) products, which include corticotropin, melanocyte-stimulating have been shown to interact with the immune system (Jessop 1998; Lipton and Catania 1998). In the adrenal gland cortico- tropin stimulates the release of glucocorticoids, typically cortisol in man and corticosterone in rodents. The responses of the hypothalamic-pituitary-adrenal (HPA) axis are regulated by an efficient negative feedback system, exerted by glucocorticoids. Activation of the HPA axis is also seen in responses to stress involving activation of the immune system. The cytokine inter- leukin-1 induces the secretion of CRF and corticotropin (Sapol- sky et al 1987) via the interleukin-1 type I receptors, stimulating glucocorticoid secretion, and thus interacting with the negative feedback mechanism (Turnbull and Rivier 1999). Taken to- gether, the endocrine and immune system are interrelated via a bidirectional network in which hormones affect immune function and immune responses are complementary by neu- roendocrine changes. On the physiologic level, PTSD has been associated with disordered levels of circulating cortisol (increased in some studies and decreased in others; Bremner et al 1997; Delahanty et al 2000; Elzinga et al 2003; Mason et al 1986, 1988; McFarlane et al 1997; Pitman and Orr 1990; Rasmusson et al 2001; Resnick et al 1995; Yehuda et al 1991a, 1991b, 1992, 1996; Yehuda and McEwen 2004) and with altered functioning of the immune system (Baker et al 2001; Maes et al 1999; Spivak et al 1997). Recent data show that preventive administration of cortisol reduces the incidence of cases of PTSD following septic shock (Schelling et al 1999, 2001, 2003). Another recent study found that externally admin- istered cortisol reduces PTSD symptoms in patients with chronic PTSD (Aerni et al 2004). A fundamental question is whether low basal cortisol levels represent a consequence of traumatic exposure (neurotoxic effect of trauma) or a preexisting trait that predisposes individu- als to pathological stress reactions (e.g., PTSD). One approach to evaluating this question is to employ strains of rats with different genotypically determined HPA axes and immune system responses. For this study, the histocompatibly similar Lewis and Fischer rats were selected because they differ markedly in terms of the responses of both their HPA axis and their immune system to stressogenic stimuli. There is a considerable degree of variability in individual responses to potentially traumatic events in humans and, over time, a minority of those experiencing such events are found to fulfill criteria for PTSD. In animal models, a similar phenomenon of individual variance has been observed in response to poten- tially traumatic stressogenic stimuli, and it has proved to be valuable to isolate the groups of animals with individual behav- ioral responses to the stress paradigm that are disordered in the From the Ministry of Health Mental Health Center (HC, MAM, DB, UL, NK, ZK), Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva; Chaim Sheba Medical Center (JZ), Sackler Medical School, Tel-Aviv University, Tel Hashomer, Israel; and the School of Psychology (YG), University of Southampton, Southampton, United Kingdom. Address reprint requests to Hagit Cohen, Ph.D., Anxiety and Stress Research Unit, Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 4600, Beer-Sheva 84170 Israel; E-mail: hagitc@bgu.ac.il. Received November 19, 2004; revised March 21, 2005, revised August 14, 2005; accepted September 23, 2005. BIOL PSYCHIATRY 2006;59:1208 –1218 0006-3223/06/$32.00 doi:10.1016/j.biopsych.2005.12.003 © 2006 Society of Biological Psychiatry